Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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Even though it has been recognized that arachidonic acid metabolites, eicosanoids, play an important role in the control of renal blood flow and glomerular filtration, several key observations have been made in the past decade. One major finding was that two distinct cyclooxygenase (COX-1 and COX-2) enzymes exist in the kidney. A renewed interest in the contribution of cyclooxygenase metabolites in tubuloglomerular feedback responses has been sparked by the observation that COX-2 is constitutively expressed in the macula densa area. Arachidonic acid metabolites of the lipoxygenase pathway appear to be significant factors in renal hemodynamic changes that occur during disease states. In particular, 12(S)- hydroxyeicosatetraenoic acid may be important for the full expression of the renal hemodynamic actions in response to angiotensin II. Cytochrome P-450 metabolites have been demonstrated to possess vasoactive properties, act as paracrine modulators, and be a critical component in renal blood flow autoregulatory responses. Last, peroxidation of arachidonic acid metabolites to isoprostanes appears to be involved in renal oxidative stress responses. The recent developments of specific enzymatic inhibitors, stable analogs, and gene-disrupted mice and in antisense technology are enabling investigators to understand the complex interplay by which eicosanoids control renal blood flow.
cyclooxygenase; lipoxygenase; cytochrome P-450; prostaglandins; tubuloglomerular feedback; endothelial-derived hyperpolarizing factor; angiotensin II; endothelin; nitric oxide
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INTRODUCTION |
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ARACHIDONIC ACID THAT IS ESTERIFIED at the sn-2 position of the glycerol backbone of membrane phospholipids can be released intracellulary, then enzymatically converted to a family of metabolites known as eicosanoids. Three major enzymatic pathways, cyclooxygenase (COX), lipoxygenase, and cytochrome P-450 (CYP450), are responsible for the generation of biologically active eicosanoids. The arachidonic acid metabolites formed are determined by factors including species, tissue, and hormonal background. In recent years, studies have provided convincing evidence that metabolites of the major enzymatic pathways contribute importantly to the regulation of renal hemodynamics (70, 99, 110). This review will focus on the emerging concepts related to the control of renal blood flow and glomerular filtration by eicosanoids.
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COX METABOLITES: VASODILATOR PROSTAGLANDINS |
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Prostaglandins PGE2 and PGI2 are synthesized by vascular and tubular structures throughout the kidney and regulate renal hemodynamics and tubular transport function (23, 110, 142). Overall, the COX metabolites PGE2 and PGI2 have been demonstrated to increase renal blood flow and glomerular filtration rate (70, 110). Iloprost, a PGI2 analog, increases renal blood flow and decreases urinary sodium excretion when administered into the dog renal artery (165). The antinatriuretic effect of iloprost appears to be due to its effect on arterial pressure because the PGI2 analog causes natriuresis when administered at a dose that does not decrease arterial pressure (70, 110, 165). Direct comparison of the two prostaglandins has demonstrated that the renal vasodilatory response to PGI2 is approximately one-half that demonstrated to PGE2 (165). Similarly, the PGE2 analog viprostol is a more potent renal vasodilator compared with iloprost (31). Besides increasing renal blood flow, PGE2 elicits increases in sodium excretion and renal interstitial hydrostatic pressure, suggesting a role for this prostanoid in natriuretic responses (110, 131, 165).
The regulation of water and electrolyte homeostasis by prostaglandins is partly mediated through their renal hemodynamic actions. A number of studies have demonstrated that the increase in sodium excretion in response to increased renal perfusion pressure is markedly attenuated by inhibition of the COX pathway (90, 110, 132). The natriuretic response to increasing renal interstitial hydrostatic pressure is blunted by indomethacin or meclofenamate (110, 131), but not during COX-2 inhibition (51), suggesting involvement of a COX-1-derived metabolite. PGE2 may be the COX-derived metabolite that mediates pressure-induced natriuresis because PGE2 is a renal vasodilator and inhibits epithelial sodium transport in the medullary thick ascending limb (mTAL) and cortical collecting duct (131, 132, 165). The actions of PGE2 on renal medullary blood flow could also explain its contribution to the pressure-natriuretic response (131, 148). PGE2 dilates endothelin-precontracted isolated outer medullary descending vasa recta vessels where PGE2 is synthesized by neighboring collecting duct epithelial and interstitial cells (148). Additionally, intrarenal infusion of PGE2, but not PGI2, restores the pressure-natriuretic response during COX blockade (70, 110). Thus PGE2 is necessary for the full expression of the pressure-natriuretic response and is important for the kidney's ability to maintain water and electrolyte balance.
PGE2 is the major renal COX metabolite in the kidney, and the PGE2 receptors (EP) are the most abundant prostanoid receptors in the kidney (22, 23, 70, 110). Four seven-transmembrane-spanning domain receptor subtypes have been identified, and the cDNA for each EP receptor has been determined (22, 23). Renal localization of the mRNA and immunohistochemical expression for the EP receptors have been studied. Collecting ducts of the cortex and papilla contain the EP1 receptor, and tubules of the outer medulla and cortex express the EP3 receptor (151). The EP2 receptor protein is also detectable in the media of human renal arteries and arterioles (101). High levels of EP3 receptor mRNA expression is localized to the mTAL, with lower levels detected in the cortical collecting duct (23, 101, 158). Glomeruli also have been demonstrated to have strong EP3 protein expression in the human kidney (101). The EP4 receptor is expressed in the glomerulus, media of renal arteries, and renin-secreting juxtaglomerular granular cells, with lower levels of expression detected in the outer medulla (22, 24, 101). This renal localization of the EP receptors is intimately associated with the specific physiological actions of PGE2.
Characterization of the EP receptors and their intracellular signaling mechanisms have been extensively studied in nonrenal cells, but the contribution of these receptors to the control of renal blood flow remains unresolved. Renal vascular smooth muscle cells contain the receptor protein for the EP1 and EP3 receptors (22). Because EP1 and EP3 receptor activation stimulates cellular signaling mechanisms that would oppose vasodilation, these receptors may antagonize the PGE2-mediated increase in renal blood flow. Activation of the EP1 receptor stimulates phosphatidylinositol hydrolysis, resulting in receptor-operated calcium mobilization, and evidence suggests that PGE2 acts through the EP1 receptor in rabbit cortical collecting duct cells to inhibit sodium transport (58, 59). PGE2 activation of the EP1 receptor causes vascular smooth muscle contraction in a variety of tissues and may be responsible for the PGE2-evoked increase in intracellular calcium observed in cultured mesangial cells (22, 36). Early studies that localized the EP3 receptor to the mTAL cells and cortical collecting duct focused investigation on its contribution to tubular transport processes (22, 23). The EP3 receptor signals via pertusssis toxin-sensitive Gi and inhibition of adenylate cyclase and may oppose the vasodilatory response to PGE2 (22, 170). This possibility has been suggested by studies in EP3 gene-disrupted mice that show a prolonged systemic vasodepressor response to PGE2 administration that is more pronounced in male mice (10). EP3 receptor activation may also have renal hemodynamic actions because misoprostol, an EP2-, EP3-, and EP4-receptor agonist, causes a slight vasoconstriction and decreased glomerular filtration rate in humans (109). Additionally, mice that lack the EP3 receptor have elevated renal blood flows compared with wild-type mice (9). This is consistent with the renal vasoconstriction to PGE2 seen in the juxtamedullary vasculature of the rat (75) and supports the concept that the EP1 and EP3 receptors contribute to the control of renal blood flow.
EP2 and EP4 receptors will be considered together because they share similar signaling and physiological characteristics. Stimulation of these EP receptors activates Gs coupled to adenylate cyclase and elevates intracellular cAMP levels in rabbit and rat preglomerular vessels (22, 23, 33, 135). PGE2 stimulates cAMP production, resulting in mesangial cell relaxation, and is thought to be the mechanism by which PGE2 causes an increase in glomerular filtration rate (100). Disruption of the EP2 receptor in mice does not alter renal blood flow or vascular resistance (9) but unmasks a systemic vasoconstriction in response to PGE2 (85). PGE2 also vasoconstricts the afferent arterioles of EP2 receptor-deficient mice (66). These mice lacking an EP2 receptor develop hypertension when fed a high-salt diet (85). Investigation of EP2 receptor regulation is of extreme interest because the vascular and transport effects of PGE2 are altered in renal pathophysiological states.
PGI2 exerts its biological effects via stimulation of the PGI2 receptor (IP) found throughout the renal cortex and medulla (22, 70, 110). The IP receptor is a seven-transmembrane-spanning receptor coupled to the generation of intracellular cAMP (22). PGI2 dose dependently stimulates adenylate cyclase activity in freshly isolated preglomerular vessels (33, 135). Cicaprost and iloprost are PGI2 analogs that selectively activate the IP receptor and vasodilate the glomerular microvasculature (31, 32, 110). IP receptor activation is not as effective as EP receptor activation in causing renal vasodilation (31, 32, 165). Even with this being the case, IP receptor activation in response to PGI2 may be the primary mechanism that opposes vasoconstrictor agonists because renal vascular smooth muscle cell PGI2 production is substantially greater than that of PGE2 (126).
Studies investigating PGE2, PGI2, or analogs of
these COX metabolites have demonstrated that vasodilatory
prostaglandins oppose the effects of renal vasoconstrictors (17,
31, 32, 126). Renal hemodynamic interactions between
prostaglandins and angiotensin II have been extensively studied (Fig.
1). Angiotensin II increases the
production of prostaglandins by the kidney (110, 126), and these COX metabolites buffer the angiotensin II-mediated decrease in
renal blood flow (31, 32, 79). Although prostaglandins buffer the whole kidney renal blood flow responses to angiotensin II,
there may be differences between superficial and juxtamedullary afferent arteriolar populations. Microdissected superficial afferent arterioles demonstrate an enhanced responsiveness to angiotensin II
during COX inhibition (81, 179). In contrast, the
angiotensin II vasoconstrictor response of juxtamedullary afferent
arterioles (67) and descending vasa recta is not altered
by COX blockade (56). The cellular signaling mechanism by
which prostaglandins modulate the cytosolic calcium response to
angiotensin II has been investigated by using cultured renal arteriolar
vascular smooth muscle cells. Purdy and Arendshorst (126)
demonstrated that the renal vascular smooth muscle cell calcium
response to angiotensin II was enhanced during indomethacin treatment.
In this study, PGE2 and PGI2 attenuated the
angiotensin II-mediated intracellular calcium response
(126). These results suggested that a vascular smooth
muscle cell-derived COX metabolite was involved in the angiotensin
II-induced calcium response (Fig. 1). Although prostaglandins are
considered to be primarily endothelial derived, renal preglomerular
vascular smooth muscle cells produce PGE2 and
PGI2 (87, 126). Renal vascular smooth muscle
cell PGI2 production is greater than that of
PGE2, and angiotensin II increases the production of these
prostaglandins (126). Taken together, these studies
suggest that endothelial- and vascular smooth muscle cell-derived
vasodilatory prostaglandins activate adenylate cyclase and attenuate
the renal vascular response to angiotensin II.
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Similarly, vasodilator prostaglandins have been implicated in the modulation of the vasoconstrictor responses to norepinephrine and vasopressin. Norepinephrine stimulates the release of prostaglandins from the kidney (76, 110). The renal vasoconstrictor response to norepinephrine is enhanced by COX blockade (8, 15, 67), but addition of prostaglandin metabolites can either enhance or attenuate this response (110). Norepinephrine reactivity of isolated perfused rabbit afferent and efferent arterioles is enhanced by indomethacin (8, 67). This modulation of the afferent arteriolar vasoconstriction in response to norepinephrine appears to be mediated via the COX-2 enzyme because the decrease in vascular diameter is enhanced to the same extent by the nonselective COX inhibitor indomethacin or the COX-2 inhibitor NS-398 (67). Like norepinephrine, vasopressin stimulates renal and glomerular prostaglandin production (2, 140). In addition, systemic administration of COX inhibitors enhances and prolongs the renal vasoconstrictor response to vasopressin (15, 164). Hence, COX-derived prostaglandins contribute to the renal blood flow responses elicited by norepinephrine and vasopressin.
Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide that plays a crucial role in maintaining fluid and electrolyte homeostasis, and its response is modulated by COX metabolites (49, 118, 124). The involvement of the COX pathway in the renal vasoconstrictor response to ET-1 appears to be complex. Actions of ET-1 on the ETA and ETB receptors include phospholipase A2 (PLA2) stimulation and the resultant increase in COX-derived mediators (16, 118, 141). Oyekan et al. (118) demonstrated that the ET-1-evoked decreases in renal blood flow and glomerular filtration rate were enhanced by COX blockade when studied in vivo. The same group of investigators showed in the isolated perfused kidney that COX inhibition attenuated the renal vasoconstrictor response to ET-1 (117). In a recent study, the COX inhibitor indomethacin attenuated the afferent arteriolar decrease in diameter and renal microvascular smooth muscle cell calcium response to ET-1 (72). Because indomethacin had a greater effect in the juxtamedullary preparation with an intact endothelium than in freshly isolated vascular smooth muscle cells, these results suggest that endothelial-derived COX vasoconstrictor metabolites contribute importantly to the ET-1-mediated afferent arteriolar response (72). The opposing findings of interactions between COX and ET-1 may be due to the absence of bloodborne elements such as platelets or sympathetic innervation when studied in vitro. The relative influence of ETA and ETB receptors could also be different with the ETA receptor-mediated activation of arachidonic acid pathways predominating under certain experimental conditions. These paradoxical findings demonstrating positive and negative contributions of COX-derived metabolites to ET-1 are not limited to the kidney (40, 92, 141) and most likely reflect in vitro vs. in vivo experimental conditions and the prevailing COX metabolites.
On the other hand, renal vasodilatory responses to bradykinin and
acetylcholine have been demonstrated to involve the generation and
actions of prostaglandins (70, 110) (Fig.
2). Bradykinin has been demonstrated to
increase the renal production of prostaglandins, and one-third of the
bradykinin-mediated vasodilation is prostaglandin dependent
(98). Release of endothelial PGI2 and nitric
oxide occurs after acetylcholine administration (43), and
combined COX and nitric oxide blockade prevents the
acetylcholine-induced increase in renal blood flow (177).
Interestingly, the actions of COX and nitric oxide overlap, and one
system can fully compensate for the other.
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COX METABOLITE: THROMBOXANE |
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Thomboxane A2 (TxA2) and PGH2 are two vasoconstrictors produced in small quantities by the kidney under normal physiological conditions (120). A major renal site for TxA2 synthesis is the glomerular mesangial and podocyte cells (70, 93, 142). COX-derived vasoconstrictors act on thromboxane/enderperoxide (TP) receptors and influence renal hemodynamics to a greater extent during pathophysiological states (70, 110, 149). Administration of TxA2 analogs either in vivo or in vitro has been consistently shown to decrease renal blood flow and glomerular filtration rate, but the relative influence on pre- and postglomerular resistance could not be resolved in studies evaluating whole kidney hemodynamics (70, 110). Hayashi et al. (57) directly evaluated the actions of the TxA2 mimetic U-44069 on afferent and efferent arteriolar diameter in the isolated perfused rat hydronephrotic kidney. These investigators found that U-44069 constricted the afferent arteriole to a greater degree than the efferent arteriole (57). TxA2 and TxA2-mimetic actions are the result of TP receptor activation because TP-receptor antagonists block all the renal hemodynamic effects of these agents (70, 110).
The primary TP receptor (TPa) has been cloned and is expressed in the kidney (1, 61). Human intrarenal arteries and glomeruli have also been demonstrated to possess TP receptors (25). TPa and the splice variant TPK are coupled to Gq that signals through phospholipase C (PLC), resulting in elevated intracellular inositol triphosphate (IP3) levels and mobilization of calcium from intracellular stores (115, 128). This signaling pathway has been demonstrated in cultured rat glomerular mesangial cells that respond to the TxA2 mimetic U-46619 by increasing cellular IP3 and calcium levels (150). Like other vasoconstrictors, TP receptor-mediated decreases in afferent and efferent arteriolar diameter are the result of activating different intracellular signaling mechanisms. Afferent arteriolar vasoconstriction in response to U-44069 is blocked by L-type calcium channel inhibition (57). In contrast, the smaller decrease in efferent arteriolar diameter evoked by TP receptor activation is unaltered by the presence of the L-type calcium channel inhibitors diltiazem or nifedipine (57). Thus TxA2-mediated afferent arteriolar vasoconstriction involves calcium influx via L-type channels, whereas the decrease in efferent arteriolar diameter is independent of L-type calcium channel activation.
TP receptor activation can also contribute to the angiotensin II-mediated renal vasoconstriction. Involvement of TxA2 and TP receptor activation in the renal vascular actions of angiotensin II has been associated with conditions in which the renin-angiotensin system is elevated and circulating angiotensin II levels are high (70, 110). Along these lines, kidney TxA2 synthesis increases during various renal disorders including nephritis, cyclosporin nephrotoxicity, and renal transplant rejection (70, 110). A recent study demonstrated that ureteral obstruction led to a greater intratubular pressure in TP receptor-deficient mice compared with wild-type mice, suggesting that TxA2 is an important regulator of renal vascular tone in this pathological state (145). Therefore, TP-receptor antagonists have possible clinical utility in the treatment of renal hemodynamic dysfunction, particularly when the renin-angiotensin system is activated.
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COX METABOLITES: RENAL BLOOD FLOW AND FLUID-ELECTROLYTE HOMEOSTASIS |
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The extremely efficient autoregulation of renal blood flow and glomerular filtration rate is the result of the complicated interplay between both the tubuloglomerular feedback and myogenic responses of the renal microvasculature (70, 110). The contribution of COX metabolites to renal blood flow autoregulation has been studied by using inhibitors of COX in a number of species. In cases where renal blood flow autoregulation has been assessed, COX inhibition has failed to alter the autoregulatory responses to changes in perfusion pressure (70, 110). Nevertheless, COX metabolites may be involved in the modulation of tubuloglomerular feedback responses. Several micropuncture studies have demonstrated that COX inhibition blunts tubuloglomerular feedback responses (123, 144, 171). In addition, tubular prostaglandin infusion alters the sensitivity of the tubuloglomerular feedback response (70, 110). Systemic or tubular perfusion of TxA2 mimetic U-46619 enhanced the sensitivity of the tubuloglomerular feedback response (172). The TxA2 mimetic has also been demonstrated to enhance the tubuloglomerular feedback response in wild-type mice but does not alter this response in TP receptor-deficient mice (145). Interestingly, TP receptor gene disruption did not attenuate the tubuloglomerular feedback response under control conditions (145). Thus COX metabolites do not appear to mediate renal autoregulatory responses but do have modulatory influence on tubuloglomerular feedback responses. Interest in the involvement of the COX pathway and renal autoregulatory responses has been revitalized by the discovery of COX-2 in the macula densa and adjacent epithelial cells (55, 178).
Gene-disruption studies would appear to be ideally suited to
investigations aimed at determining the contribution of COX-1 and COX-2
on renal blood flow autoregulatory responses. This has not been the
case because COX-derived metabolites are essential for neonatal
development and reproduction. COX-1-deficient mice have delayed
maturation, and pups do not survive past postpartum day 1 (11). This phenotype can be rescued by PGF2
injection at term (11). COX-2-deficient mice develop
severe nephropathy linked to impaired nephron maturation (39,
102). These phenotypic consequences of COX enzyme deficiency
have precluded studies designed to evaluate renal blood flow and fluid
electrolyte homeostasis in COX gene-disrupted mice. Development of
organ-targeted, COX gene-disrupted mice should prove more useful in
evaluating the influence of COX-1 and COX-2 metabolites on renal
vascular and tubular function. Therefore, investigations have relied on
pharmacological agents that selectively inhibit either COX-1 or COX-2.
Recently, interactions between COX-2 and neuronal nitric oxide synthase
(nNOS) have been observed for afferent arteriolar tubuloglomerular
feedback responsiveness (Fig. 3)
(62, 63). Nitric oxide is an oxidizing radical that
interacts with heme-containing proteins like COX (64).
COX-2 and nNOS are constitutively expressed predominantly in and around
the macula densa (12, 55, 173, 178). This unique
localization suggested that these enzymes could interact and play an
important role in tubular flow-dependent responses. Recent studies
conducted by Ichihara et al. (62, 63) demonstrated that,
during increased tubular flow past the macula densa, increased
nNOS-derived nitric oxide dilates the preglomerular vasculature
directly and stimulates COX-2 vasodilatory prostaglandin production.
Therefore, the increased levels of nitric oxide and prostaglandins
buffer the magnitude of the tubular glomerular feedback-mediated
afferent arteriolar vasoconstriction.
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As previously discussed, COX-derived metabolites interact with and modulate the renal hemodynamic responses to angiotensin II. Metabolites of COX pathways can also modulate the renin-angiotensin system by altering kidney renin production. Numerous studies have suggested a role for COX-derived prostaglandins in the regulation of renal renin secretion. Overall, prostaglandins have been demonstrated to stimulate renin release from kidneys (Fig. 3), and COX inhibition suppresses renin production (70, 110). Prostaglandins appear to mediate renin release during macula densa activation (50, 161, 174). In the isolated perfused rabbit juxtaglomerular apparatus preparation, COX-2 inhibition nearly abolished renin release in response to decreases in luminal NaCl (161). In support of the concept that COX-2-derived metabolites mediated renin secretion, Harding et al. (54) demonstrated that COX-2 inhibition prevented the increase in renal renin mRNA in animals fed a low-salt diet. Renal cortical COX-2 mRNA expression also increases in animals placed on a low-salt diet, and angiotensin-converting enzyme inhibition or angiotensin II type 1 receptor (AT1) blockade enhances the increase in COX-2 (174). This study suggests that angiotensin II acts as a negative feedback controller that limits the stimulation of COX-2 and renin synthesis during low dietary salt intake. Overall, these studies suggest that an interaction between the renin-angiotensin system and COX-2 may contribute to the regulation of renal hemodynamics in response to salt depletion.
In support of the concept that an interaction between angiotensin II and COX-2 may contribute to renal hemodynamic function, renal blood flow and glomerular filtration rate decreased transiently in salt-depleted individuals given 400 mg/day of the COX-2 selective inhibitor celecoxib (134). The influence of COX-2 on renal hemodynamics in humans depends on salt intake because glomerular filtration rate does not change during COX-2 inhibition in subjects on a normal-salt diet (30). In contrast, acute administration of the COX-2 inhibitor MF-tricyclic did not alter renal blood flow in volume-depleted dogs (18). Although these studies suggest that macula densa COX-2-derived metabolites are essential for the kidneys response to dietary salt, the profile of prostaglandins produced by the macula densa cells is unknown. A recent study provides evidence that renal cortical PGE2 stimulates renin secretion and maintains renal blood flow during salt depletion (80). Additionally, PGE2 activation of EP4 receptors may preserve renal hemodynamic function because EP4 receptors are upregulated in isolated glomeruli, mesangial cells, and juxtaglomerular granular cells in response to low dietary salt (80). Therefore, COX-2-derived metabolite production is regulated and localized to the structure in the kidney that plays an essential role in renal blood flow and fluid-electrolyte homeostasis.
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LIPOXYGENASE METABOLITES |
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The lipoxygenase enzymes metabolize arachidonic acid to form leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), and lipoxins (LXs). Lipoxygenase metabolites are primarily produced by leukocytes, mast cells, and macrophages in response to inflammation and injury (70, 110). The 5-lipooxygenase enzyme (5-LO) that synthesizes LTs has limited cellular distribution and has been found in leukocytes, mast cells, and macrophages (35). Although LTs are primarily produced by leukocytes, the glomerular mesangial cells and endothelial cells contain LTA4-hydrolase that converts LTA4 to LTB4 (2, 13, 110). Glomeruli, mesangial cells, cortical tubules, and vessels also produce the 12-lipoxygenase (12-LO) product 12(S)-HETE and the 15-LO product 15-HETE (2, 13, 78). Gene expression of 5-LO, 12-LO, and 15-LO has been detected in cultured glomerular cells (91). Additionally, leukocyte-generated LTA4 can be transformed to LXs via 12-LO in the glomerulus and endothelial cells (13). These lipoxygenase metabolites have effects on renal hemodynamics and glomerular filtration and have been implicated in inflammatory diseases and glomerulonephritis (70, 110).
The lipoxygenase metabolites, 12(S)-HETE, 15-HETE, LTs, and LXs, are involved in inflammatory responses and have effects on renal hemodynamics (13, 82, 96, 110). The lipoxygenase products 12(S)-HETE and 15-HETE are potent glomerular and renal vascular vasoconstrictors. 12(S)-HETE decreases renal blood flow and glomerular filtration independently of COX activity (82). Although 12(S)-HETE causes depolarization of the vascular smooth muscle cell membrane and may act through activation of PKC (96), the mechanism by which 12(S)-HETE constricts the preglomerular vasculature remains to be identified. In a recent study, the afferent arteriolar vasoconstriction and increase in renal microvascular smooth muscle cell calcium, in response to 12(S)-HETE, were greatly attenuated by diltiazem treatment (73). These results suggest that activation of voltage-gated L-type calcium channels is an important mechanism responsible for the renal vasoconstriction elicited by 12(S)-HETE.
The 12-LO product, 12(S)-HETE, appears to be critically involved in regulating angiogenesis and atherosclerosis. In various endothelial cell lines, 12-LO inhibition reduces cell proliferation and growth factor release, whereas overexpression of 12-LO stimulates cell migration and endothelial tube formation (112). Similarly, disruption of the 12/15-LO gene diminishes atherosclerotic lesions in apo E-deficient mice (38). Elimination of the leukocyte 12-LO enzyme in mice also ameliorates the development of streptozotocin diabetes (19). 15-LO appears to protect renal function during glomerulonephritis because transfection of rat kidney with human 15-LO enzyme suppresses inflammation and preserves glomerular filtration (106). Hence, 12-LO and 15-LO metabolites appear to protect the kidney during various inflammatory diseases.
LXs also increase renal vascular resistance and may act through activation of LT receptors (13, 82). LXA4, LXB4, and 7-cis-11-trans-LXA4 when administered into the renal artery cause vasoconstriction (82). The actions of LXA4 are COX dependent, whereas the effect of LXB4 on renal hemodynamics is independent of COX activity (82). LTD4 receptor blockade abolished the 7-cis-11-trans-LXA4 renal vasoconstrictor response and demonstrates that the response was due to activation of a LT receptor (82). LTC4 and LTD4 also increase renal vascular resistance and decrease glomerular filtration rate when administered into the renal artery (13, 14, 110). The cellular signaling mechanisms utilized by LTs are better understood because LT receptors have been identified and characterized. Activation of the LTC4 and LTD4 receptors by their endogenous ligands results in renal and glomerular vasoconstriction (14, 110). In accordance with a role for LT receptors in glomerular inflammatory responses, LTC4 has been shown to stimulate mesangial cell growth (13, 91). The effects of inhibition of LT receptors to decrease glomerular capillary pressure suggest that LTs constrict the efferent arteriole to a greater extent then the afferent arteriole (14).
Recently, a seven-transmembrane-spanning cysteinyl leukotriene receptor (CysLTR) implicated in inflammatory disorders has been identified and characterized in human embryonic kidney (HEK-293) cells (138). LTs activate the CysLTR expressed in HEK-293 cells, resulting in mobilization of intracellular calcium (138). Two CysLTRs have been found on the vascular smooth muscle and endothelium of the pulmonary vasculature (166). Another LT receptor that has recently been cloned and characterized in the rat is the LTB4 receptor (160). When expressed in HEK-293 cells, the LTB4 receptor demonstrated specific and high-affinity binding to LTB4 (160). The LTB4 receptor has been implicated in acute renal ischemic-reperfusion injury (113), and LTB4 receptor blockers ameliroate nephrotoxic nephritis in rats (155). Moreover, polymorphonuclear neutrophil recruitment and reperfusion injury are greatly amplified in transgenic mice overexpressing the LTB4 receptor (34). The contribution of CysLTRs and LTB4 receptors to influence renal hemodynamics and their role in pathophysiological states remains to be determined.
Interactions between lipoxygenase metabolites and renal vasoactive autocoids have been investigated. The involvement of the lipoxygenase metabolite 12(S)-HETE in the renal vasoconstrictor response to angiotensin II has been demonstrated in several studies (Fig. 1) (17, 67, 107, 114). A study performed by Bell-Quilley et al. (17) demonstrated that, in the isolated perfused rat kidney, inhibition of the 12-LO pathway attenuated the angiotensin II-mediated decrease in renal blood flow. That angiotensin II, but not norepinephrine, evoked vasoconstriction of the afferent arteriole has also been demonstrated to be attenuated by the lipoxygenase inhibitor baicalein (67). Attenuation of the vasoconstrictor response to angiotensin II, but not norepinephrine, has also been demonstrated for large arteries of the skeletal muscle and pulmonary vasculature (84, 107). In contrast, lipoxygenase inhibition attenuated the renal arcuate artery vasoconstrictor response to norepinephrine and KCl but had no effect on the vascular response to ET-1 (177). Interactions between LTs and the vasodilator nitric oxide have been shown in isolated perfused renal arteries and veins (121, 122). Specifically, LTD4 vasodilation of renal arteries was demonstrated to be endothelial dependent and mediated by nitric oxide (122). Thus much remains to be learned about the actions of lipoxygenase metabolites on renal hemodynamics even though these metabolites play a key role in glomerular nephritis and inflammatory diseases.
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CYP450 METABOLITES |
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The metabolism of arachidonic acid by CYP450 enzymes in the kidney has been recognized for several years and displays one of the highest organ CYP450 activities (65, 99, 110, 127). The kidney possesses two CYP450 monooxygenase pathways that metabolize arachidonic acid to generate epoxyeicosatrienoic acids (EETs) that are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) and HETEs (26, 70, 99). CYP450 monooxygenases are mixed-function oxidases that depend on molecular oxygen and NADPH as cofactors (26). EETs and DHETs are formed primarily via CYP450 epoxygenase enzymes, and HETEs are formed primarily via CYP450 hydroxylase enzymes (99, 110). CYP450 enzymes are distributed throughout the kidney vasculature and tubular segments, and arachidonic acid metabolites of the CYP450 pathway have an impact on renal hemodynamics (65, 99, 110, 127).
Production of EET, DHET, and HETE occurs throughout the kidney, but the specific metabolites formed and the amounts produced of each metabolite vary depending on the cell type and CYP450 isoform expressed. The CYP450 4A gene family is the major pathway for synthesis of hydroxylase metabolites (99, 129, 168), whereas the production of epoxygenase metabolites is primarily via the 2C gene family (26, 65). Another epoxygenase-producing enzyme family, CYP450 2J, was initially demonstrated to be present in the lung epithelial and vascular smooth muscle (180). Members of the 2J family actively produce EETs and midchain HETEs, and the transcripts are most abundant in the mouse kidney and present in lower levels in the liver (94). In situ hybridization revealed that the CYP450 2J protein was present in the proximal tubules and collecting ducts of the renal cortex and outer medulla (94). Several other enzymes, including CYP450 2E1 and 2B1/2, are present in proximal and distal tubule cells, but their functional roles remain to be resolved (37). The specialized tissue distribution and expression of various renal CYP450 epoxygenase and hydroxylase isoforms capable of producing EETs, DHETs, and HETEs allow for site-specific regulation and action. The production of epoxygenase and hydroxylase metabolites by the kidney is regulated by hormonal and paracrine factors, including angiotensin II, endothelin, parathyroid hormone, and epidermal growth factor (65, 70, 99, 110, 127, 129). Regulation of renal CYP450 activity is also importantly involved in the kidney response to changes in dietary salt intake (26, 65, 129). Additionally, alterations in the production of CYP450 metabolites occur after uninephrectomy, the induction of diabetes mellitus, and during the development of hypertension (26, 65, 127). Investigations are beginning to describe some of the changes in and regulation of specific CYP450 isoforms that may be associated with alterations in renal hemodynamics that occur during various pathophysiological states.
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CYP450 HYDROXYLASE METABOLITE: 20-HETE |
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Renal arterioles, glomeruli, and pericytes surrouding vasa recta capillaries contain CYP450 4A enzymatic protein that is primarily responsible for the formation of 20-HETE (74, 77, 116, 127, 168). RT-PCR analysis of microdissected rat renal microvessels revealed the presence of CYP450 4A1, CYP450 4A2, and CYP450 4A3 mRNAs (74, 168). Interestingly, intravenous administration of antisense oligonucleotides against CYP450 4A1 or CYP450 4A2/4A3 markedly inhibited renal preglomerular vascular 20-HETE synthesis and implicated CYP450 4A1 as the major 20-HETE-forming isoform (168). Although earlier studies have produced conflicting data concerning the contribution of CYP450 hydroxylase metabolites to the control of renal hemodynamics, many of these conflicts have been recently resolved and a better understanding has emerged. 20-HETE is a potent vasoconstrictor of the preglomerular arterioles and may contribute importantly to the renal blood flow autoregulatory responsiveness of the afferent arteriole (99, 110, 129). The actions of 20-HETE on hemodynamics appear to be paracrine and autocrine in nature rather than by the exertion of its effects humorally or systemically (99, 110, 129).
The CYP450 -hydroxylase product 20-HETE has been demonstrated to be
a renal vasoconstrictor, but under certain experimental conditions it
causes vasodilation. 20-HETE vasodilated the isolated perfused rabbit
kidney preconstricted with phenylephrine, and this vasodilation was
determined to be COX dependent (29). In contrast, 20-HETE
vasoconstricted the rabbit afferent arteriole preconstricted with
norepinephrine (7). 20-HETE also resulted in
vasoconstriction of the rabbit renal artery that was partially dependent on an intact endothelium and metabolism via COX
(41). Dog renal arteries and rat afferent arterioles of
the juxtamedullary region and isolated perfused rabbit afferent
arterioles vasoconstrict in response to 20-HETE (74, 95).
In the rat, the afferent arteriolar vasoconstriction to 20-HETE is COX
independent (74), whereas about one-fourth of the
vasoconstriction to 20-HETE in the rabbit afferent arteriole is
mediated by an endothelial-dependent COX pathway (7). The
COX-dependent responses most likely reflect the transformation of
20-HETE to vasodilatory metabolites 20-OH PGE2 and 20-OH
PGI2 or vasoconstrictor metabolites 20-OH PGH2 and 20-OH TxA2 (99). Thus the direction of the
COX-dependent vascular response may depend on the prevailing
prostaglandin isomerase that transforms 20-HETE. Recently, stable
agonistic analogs of 20-HETE have been synthesized by Dr. J. R. Falck, and these 20-HETE analogs vasoconstrict the rat preglomerular
vasculature (4). In the future, these 20-HETE analogs will
be valuable investigative tools for determining cellular signaling
mechanisms used by 20-HETE and its role in renal hemodynamic function.
To date, no evidence has been presented for the existence of cell membrane-bound 20-HETE receptors. More likely, 20-HETE acts within the cell where it is produced or within a closely associated cell, a manner similar to the way nitric oxide acts. Investigations have evaluated the cellular signaling mechanisms utilized by 20-HETE to vasoconstrict the renal vasculature. The renal arcuate artery vasoconstrictor response to 20-HETE was demonstrated to be associated with membrane depolarization and a sustained rise in intracellular calcium in vascular smooth muscle cells isolated from this artery (95). 20-HETE afferent arteriolar vasoconstriction was abolished by K+ channel blockade, and 20-HETE inhibited a renal microvascular smooth muscle cell 250-pS Ca2+-activated K+ channel (KCa) recorded by cell-attached patch-clamp techniques (74, 181). More recently, Sun et al. (153) demonstrated that 20-HETE increased expression of extracellular signal-regulated kinases (ERK) and that tyrosine kinase inhibition greatly attenuated the renal arteriolar vasoconstriction to 20-HETE. These recent data suggest that activation of tyrosine kinase and subsequent closing of KCa channels is the cellular mechanism by which 20-HETE vasoconstricts afferent arterioles.
The contribution of the CYP450 metabolite 20-HETE to the renal vasodilator response to nitric oxide was recently evaluated (Fig. 2). In the renal microcirculation, 70-75% of the nitric oxide-mediated vasodilation has been demonstrated to be cGMP independent (3, 5, 152). CYP450 inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) abolished the cGMP-independent renal arteriolar vasodilation to nitric oxide donors, suggesting that nitric oxide increases renal blood flow via inhibition of the vasoconstrictor CYP450 metabolite 20-HETE (3, 5). Nitric oxide inhibits renal microvessel formation of 20-HETE, and this could be due to nitric oxide's ability to bind heme and inhibit CYP450 enzymes (5, 152). Indeed, nitric oxide has been shown to bind the heme moiety of CYP450 4A enzymes and inhibit formation of 20-HETE (152). Similarly, chronic inhibition of nitric oxide with nitro-Larginine methyl ester for 10 days increases 20-HETE formation and CYP450 4A protein levels but had a very slight effect on epoxygenase activity (119). Because 20-HETE vasoconstricts the renal vasculature by inhibiting KCa channels (74, 181), a decrease in 20-HETE levels in vascular smooth muscle would lead to activation of KCa channels. Thus the nitric oxide-elicited renal vasodilator actions appear to be mediated through its effects to elevate cGMP levels and decrease 20-HETE formation.
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CYP450 EPOXYGENASE METABOLITES |
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The kidney has the ability to produce epoxygenase metabolites primarily via CYP450 enzymes of the 2C gene family (26, 65). CYP450 4A2 and CYP450 4A3 expressed in sF9 insect cells have also been shown to form 11,12-EET, suggesting that these isoforms may contribute to renal vascular epoxygenase production (169). Microsomes prepared from renal microvessels and vessels of other organ beds metabolize arachidonic acid to EETs (53, 74, 130, 169, 183). Although receptors for EETs have not been identified, specific binding of 14,15-EET in monocytes has been demonstrated (175, 176). EETs can also be incorporated into vascular smooth muscle and endothelial cell membranes (162, 163), suggesting that epoxygenase metabolites may have long-lasting effects or can be released after hormonal activation. Like CYP450 hydroxylase metabolites, epoxygenase metabolites of arachidonic acid effect renal blood flow and glomerular filtration rate by acting locally (65, 70, 110). 11,12-EET and 14,15-EET vasodilate the preglomerular arterioles independently of COX activity, whereas 5,6-EET and 8,9-EET cause COX-dependent vasodilation or vasoconstriction (47, 71, 156). These COX-dependent effects may be the result of 5,6-EET and 8,9-EET conversion to prostaglandin- or thromboxane-like compounds (47, 156).
Even though 11,12-EET is an excellent candidate for being an endothelium-derived hyperpolarizing factor (EDHF) in the renal microcirculation (65, 71), epoxygenase metabolites have also been found to be either renal vasoconstrictive or vasodilatory (65, 110). Infusion of 5,6-EET or 8,9-EET into the renal artery of the rat results in an increase in renal vascular resistance (156). The observed vasoconstriction was found to be COX dependent because 5,6-EET increased renal blood flow during administration of indomethacin (156). In contrast, 5,6-EET, 8,9-EET, and 11,12-EET vasodilated the isolated perfused rabbit kidney preconstricted with phenylephrine, and the vasodilation to 5,6-EET was COX dependent (28, 29). In a study that directly examined the responses of the preglomerular vasculature, it was demonstrated that 11,12-EET and 14,15-EET vasodilated, and 5,6-EET resulted in vasoconstriction of the interlobular artery and afferent arterioles (71). Additionally, it was demonstrated that the preglomerular vasoconstriction to 5,6-EET was COX dependent and required an intact endothelium, whereas the vasodilation to 11,12-EET was the result of direct action of the epoxide on the preglomerular vascular smooth muscle (71). In the dog, 11,12-EET has been shown to dilate renal arteries and activate KCa channels (182). The activation of K+ channels by 11,12-EET in the renal preglomerular vasculature appears to be mediated by cAMP stimulation of protein kinase A because the afferent arteriolar vasodilation to the sulfonimide analog of 11,12-EET was greatly attenuated by protein kinase A inhibition (69). Furthermore, the action of 11,12-EET on renal vessels and KCa channels is consistent with the possibility that this metabolite is an EDHF. 11,12-EET produced by CYP450 2C has recently been identified to be EDHF in the coronary microvasculature (42), and an epoxygenase-derived EDHF appears to mediate a large portion of the afferent arteriolar vasodilatory response to bradykinin in the isolated perfused kidneys (Fig. 2) (48).
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CYP450 METABOLITES: RENAL HEMODYNAMIC REGULATORY INFLUENCE |
---|
Besides the direct actions of CYP450 metabolites, a more important
role for these arachidonic acid products is their contribution to
modulate renal vascular responses to hormones and renal blood flow
autoregulation. A number of studies have suggested that CYP450 metabolites may participate in some component of renal blood flow autoregulation (99, 110, 129). In isolated canine arcuate arteries treated with indomethacin, arachidonic acid administration enhanced myogenic responsiveness and was blocked by CYP450 inhibition (83). Infusion of 17-ODYA into the renal artery in vivo
attenuated renal blood flow autoregulation (110, 129).
Additionally, the afferent arteriolar vasoconstriction to increasing
renal perfusion pressure was attenuated by CYP450 inhibitors, and this
attenuation was associated with impairment of glomerular capillary
pressure autoregulation (110, 129). However, selective
inhibition of the epoxygenase pathway with the imadazole derivatives
miconazole or clotrimazole had no effect on renal blood flow
autoregulation in vivo or in the isolated perfused kidney (139,
183). These studies suggest that an endogenous -hydroxylase
metabolite of arachidonic acid participates in renal blood flow
autoregulatory responses.
The lack of CYP450-selective inhibitors that can block the renal
hydroxylation and epoxidation of arachidonic acid has precluded evaluation of specific CYP450 pathways in renal autoregulatory responses. A major breakthrough by Dr. J. R. Falck's group has been the recent development of compounds that selectively inhibit renal
microsomal epoxygenase or -hydroxylase enzymatic activity (167). In a recent study, administration of the selective
hydroxylase inhibitor DDMS greatly attenuated the afferent
arteriolar vasoconstriction to increasing renal perfusion pressure
(68). In contrast, the selective epoxygenase inhibitors
6-(2-propargyloxyphenyl)hexanamide (PPOH) and
N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) enhanced afferent arteriolar diameter responses to elevations in renal perfusion pressure (68). Taken together, these
results provide further support for the concept that 20-HETE is an
integral component of the afferent arteriolar autoregulatory adjustment and that release of vasodilatory epoxygenase metabolites in response to
increases in renal perfusion pressure attenuates this preglomerular vasoconstriction.
Micropuncture studies have provided evidence that a CYP450 metabolite may be involved in the tubuloglomerular feedback response (44, 70, 129) (Fig. 3). Franco et al. (44) demonstrated that tubular perfusion of arachidonic acid simulated a tubuloglomerular feedback response. Tubular infusion of inhibitors of the lipoxygenase and COX pathways had no affect on tubuloglomerular feedback-mediated reductions in stop-flow pressure (44). Inhibition of the CYP450 pathway was demonstrated to abolish both the tubuloglomerular feedback response and the reduction in stop-flow pressure to tubular perfusion of arachidonic acid (183). Additionally, tubular perfusion of 20-HETE restores the tubuloglomerular feedback response after CYP450 inhibition (183). These studies implicate an important role for metabolites of the CYP450 hydroxylase pathway in the tubuloglomerular feedback response.
In accordance with the evidence that CYP450 metabolites are involved in tubuloglomerular feedback responsiveness, these metabolites have also been implicated in the renal maintenance of fluid and electrolyte homeostasis during changes in dietary salt (70, 99, 110). Renal cortical interstitial infusion of the nonselective CYP450 inhibitor 17-ODYA increases papillary blood flow, renal interstitial hydrostatic pressure, and sodium excretion without affecting total renal blood flow or glomerular filtration rate (184). Because both 20-HETE and EETs inhibit tubular sodium reabsorption (26, 65, 99, 129), the increased sodium excretion to CYP450 blockade appears to be secondary to the increase in renal interstitial hydrostatic pressure and papillary blood flow. An alternative explanation is that these CYP450 inhibitors cannot discriminate between the specific CYP450 4A isoforms expressed in the renal vessels and tubules and the effect of 17-ODYA on the vasculature CYP450 4A predominates. High dietary salt intake increases renal epoxygenase production and urinary excretion of EETs (26, 27). Oyekan and colleagues (119) recently demonstrated that 2% NaCl in the drinking water for 1 wk increased epoxygenase activity in the renal cortex and medulla and reduced 20-HETE formation in the cortex. The increased epoxygenase activity was also associated with upregulation of the CYP450 2C enzymes (27). Besides the direct action of EETs on the kidney to promote sodium excretion (26, 65), part of the excretory response may be attributable to the ability of 14,15-EET to inhibit renin secretion (60). Interestingly, administration of clotrimazole induced hypertension in high-salt-diet animals, suggesting an antihypertensive role for EETs (97). More recently, the production of 20-HETE and EETs by glomeruli has been shown to be decreased in rats fed a diet containing 8% NaCl (78). This study also demonstrated increased 20-HETE and CYP450 4A protein levels in the glomerulus of rats fed a low-salt diet (78). Thus the regulation of renal CYP450 production may act importantly on kidney and glomerular hemodynamics to maintain water and electrolyte homeostasis during alterations in dietary salt intake.
Previous studies have provided evidence that CYP450 metabolites may modulate responses to hormonal and paracrine agents; yet, little is known about the renal vascular interactions between these vasoactive compounds and metabolites of the CYP450 pathway. Vasopressin is one such vasoactive peptide that has been demonstrated to increase renal effluent CYP450 metabolites (164). Renal mesangial cell increases in cytosolic calcium elicited by vasopressin are amplified by epoxygenase metabolites (159). Additionally, CYP450 inhibition reduced the magnitude of the mesangial cell increase in calcium in response to vasopressin (159). 14,15-EET has also been shown to augment the ability of vasopressin to increase cultured mesangial cell thymidine incorporation (147). In the isolated perfused rat kidney, the renal vasoconstrictor response to vasopressin was attenuated by CYP450 inhibition (164). Taken together, these studies demonstrate that CYP450 metabolites contribute to glomerular proliferative and renal hemodynamic responses to vasopressin.
Like COX metabolites, CYP450 metabolites participate in the renal
hemodynamic response elicited by the powerful vasoconstrictor ET-1
(72, 117, 118). ET-1 increases renal efflux of 19-HETE and
20-HETE in the isolated perfused kidney, and the ET-1-induced increases
in renal vascular resistance are attenuated by CYP450 hydroxylase
inhibition (117, 118). More recently, it was shown that
administration of the CYP450 hydroxylase inhibitor DDMS significantly attenuated the afferent arteriolar vasoconstriction evoked by ET-1
(72). The results of this study suggest that
-hydroxylase metabolites of the CYP450 pathway contribute to the
renal vascular actions of endothelin. In contrast, ET-1-mediated
afferent arteriolar vasoconstriction was enhanced when the CYP450
epoxygenase pathway was inhibited by MS-PPOH (72). The
ability of EETs to oppose the vasoconstrictor effect does not involve
calcium regulation at the level of the renal microvascular smooth
muscle cell, because MS-PPOH did not change the intracellular calcium
response to ET-1 (72). These studies suggest that an
endothelial-derived vasodilatory EET opposes the preglomerular
vasoconstrictor activity of ET-1.
The contribution of renal microvascular smooth muscle cell signaling
mechanisms utilized by CYP450 hydroxylase metabolites to the
ET-1-mediated decrease in renal blood flow is beginning to be resolved.
In addition to attenuating the afferent arteriolar vasoconstriction,
DDMS reduced the rise in renal microvascular muscle cell calcium
elicited by ET-1 (Fig. 4)
(72). Although ETA and ETB
receptor stimulation can result in PLA2 activation and
arachidonic acid release (16, 118, 141), the ET-1 increase in calcium in freshly isolated renal microvascular smooth muscle cells
is primarily due to ETA receptor activation
(146). These studies demonstrated that a vascular smooth
muscle cell-derived CYP450 hydroxylase metabolite importantly
contributes to the ETA receptor-mediated afferent
arteriolar vasoconstriction (72, 146). Interestingly, a
CYP450 hydroxylase metabolite transformed by cyclooxygenase to a
vasoconstrictor PGH2 analog, 20-OH PGH2, may
contribute to the renal response to ET-1 (99, 117, 118). Nevertheless, the exact nature of the CYP450 hydroxylase metabolites involved in the afferent arteriolar response to ET-1 remains to be
defined.
|
Angiotensin II is another vasoactive peptide that has complex interactions with eicosanoids, including CYP450 metabolites (Fig. 1). Afferent arteriolar responses to angiotensin II, but not norepinephrine, are enhanced by nonselective inhibition of the CYP450 pathway (67). In the presence of AT1 receptor antagonism, angiotensin II causes an endothelial-dependent vasodilation in rabbit afferent arterioles that is inhibited by AT2 receptor or CYP450 blockade (6). These studies suggest that AT2 receptor activation of vasodilatory epoxygenase metabolites oppose the angiotensin II-mediated decrease in renal blood flow. On the other hand, angiotensin II has also been shown to increase 20-HETE release from isolated preglomerular microvessels (154). A preliminary report shows that 20-HETE contributes to one-half of the angiotensin II-mediated decrease in diameter in interlobular arteries with the endothelium removed (154). The CYP450 inhibitor 17-ODYA blocked angiotensin II-mediated inhibition of renal microvascular smooth muscle cell KCa channel activity (154). Taken together, these studies support the concept that angiotensin II releases a vasodilatory epoxygenase metabolite from the endothelium and the vasoconstrictor 20-HETE from the preglomerular microvasculature, which participate in the overall renal hemodynamic response.
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ISOPROSTANES |
---|
Isoprostanes are generated by peroxidation of arachidonic acid by
oxygen radicals (105). Interest in these metabolites has been fueled by studies demonstrating an elevation in the urine isoprostane 8-iso-PGF2 levels during oxidant stress and
cardiovascular disease states (70, 108, 136, 143). A
unique property of isoprostanes is that they can be formed while
arachidonic acid is still in the cell membrane (103).
Esterification of isoprostanes has been demonstrated for vascular
smooth muscle cells, mesangial cells, and renal epithelial cells
(88, 108, 136). Plasma levels of isoprostanes are
increased in spontaneously hypertensive rats and during angiotensin
II-infused hypertension (136, 143). Similarly, superoxide
dismutase mimetic administration decreases renal isoprostane excretion
and lowers blood pressure in the spontaneously hypertensive rat
(143). Oxidant injury as a result of carbon tetrachloride poisoning is also associated with tremendous elevations in isoprostane levels (70, 104). Because of their possible contribution
to renal and cardiovascular diseases, the renal hemodynamic actions of
isoprostanes have begun to be explored.
Isoprostanes decrease renal blood flow and glomerular filtration rate
by preferentially constricting the preglomerular vasculature (45,
157). Isoprostanes have also been demonstrated to potentiate the
vascular vasoconstrictor responses to angiotensin II and norepinephrine (137). The renal hemodynamic effects of
8-iso-PGF2 are completely abolished by TP receptor
antagonism, suggesting that the action of isoprostanes may be mediated
by the TP receptor (157). These effects appear to be
mediated via the TPa receptor because when the TPa receptor is
expressed in human embryonic kidney (HEK-293) cells the calcium
response to U-46619 or 8-epi PGF2
was similar and
blocked by the TP antagonists, SQ-29,548 (86). In
contrast, 8-iso-PGF2
stimulates vascular smooth muscle
cell IP3 generation and DNA synthesis at much lower
concentrations than it takes this isoprostane to displace TP receptor
ligands (45, 46, 125). The actions of
8-iso-PGF2
on vascular smooth muscle cells are only
partially blocked by TP receptor antagonism (46). Thus, taken together, these studies provide evidence suggesting the possible
existence of a novel receptor for isoprostanes.
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SUMMARY |
---|
Renal blood flow is precisely controlled to maintain glomerular filtration and fluid and electrolyte homeostasis. Eicosanoids play a critical role in the control of renal vascular resistance and are required for the proper handling of sodium and water by the body. COX-derived prostaglandins are vasodilators that modulate renal blood flow, and thromboxane is a vasoconstrictor that plays a significant role when the renin-angiotensin system is activated. Similarly, the COX-2 enzymatic isoform is an integral component that links tubular signals at the macula densa to adjustments in afferent arteriolar diameter and glomerular filtration. Metabolites of the lipoxygenase pathway can also influence renal blood flow and glomerular filtration. Although the mechanisms by which lipoxygenase metabolites control renal blood flow have not been thoroughly defined, these metabolites are significantly involved in renal hemodynamic changes that occur during disease states. The renal CYP450 pathways have been known for a number of years, and these metabolites control renal blood flow. 20-HETE is a vasoconstrictor that is a critical component of renal blood flow autoregulatory responses. Similarly, the tubular and vascular actions of epoxygenase metabolites are an important factor in the kidney's response to changes in salt diet. In addition, 11,12-EET is a renal vasodilator that has cellular signaling mechanisms consistent with its being an EDHF. Isoprostanes represent a new class of arachidonic acid metabolites that posses vasoactive properties, and these metabolites appear to be involved in renal oxidant injury. Development of experimental and pharmacological tools to selectively manipulate the renal eicosanoid system has slowly progressed. Because of the multitude of renal arachidonic acid enzymatic isoforms, the development of selective inhibitors has been difficult. This has made the study of the biological actions of eicosanoids difficult to determine experimentally. Experimental tools being developed are targeted mice, stable analogs, selective enzymatic inhibitors, antisense technology, and plasmids that overexpress specific eicosanoids. The development and incorporation of these novel pharmacological and molecular biological tools will enable investigators to better understand the contributions of eicosanoid metabolites to renal hemodynamic function.
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ACKNOWLEDGEMENTS |
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The author thanks Drs. Matthew and Richard Breyer for suggestions concerning the EP receptor section of the review.
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FOOTNOTES |
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The author's research was supported by National Institutes of Health Grants HL-59699 and DK-38226.
Address for reprint requests and other correspondence: J. D. Imig, Dept. of Physiology, SL39, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112 (E-mail: jdimig{at}tulane.edu).
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