Divisions of Nephrology and Molecular Medicine, Oregon Health Sciences University, and Portland Veterans Affairs Medical Center, Portland, Oregon 97201
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ABSTRACT |
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Following an overview of the biochemistry of mitogen-activated protein kinase (MAPK) pathways, the relevance of these signaling events to specific models of renal cell function and pathophysiology, both in vitro and in vivo, will be emphasized. In in vitro model systems, events activating the principal MAPK families [extracellular signal-regulated and c-Jun NH2-terminal kinase and p38] have been best characterized in mesangial and tubular epithelial cell culture systems and include peptide mitogens, cytokines, lipid mediators, and physical stressors. Several in vivo models of proliferative or toxic renal injury are also associated with aberrant MAPK regulation. It is anticipated that elucidation of downstream effector signaling mechanisms and a clearer understanding of the immediate and remote upstream activating pathways, when applied to these highly clinically relevant model systems, will ultimately provide much greater insight into the basis for specificity now seemingly absent from these signaling events.
urea; tubule; mesangial; extracellular signal-regulated kinase; stress-activated protein kinase; c-Jun NH2-terminal kinase; p38; mitogen-activated protein kinase
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INTRODUCTION |
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FOLLOWING AN OVERVIEW of the regulation of mitogen-activated protein kinase (MAPK) signaling, this review will focus on the relevance of these molecular events to specific models of renal physiology and pathophysiology, both in vivo and in vitro.1 As will emerge from this review, whereas the biochemistry of these pathways is being defined with increasing precision, their contribution to renal physiology and pathophysiology remains far less clear. For an in-depth review of molecular aspects of MAPK signaling, the reader is referred to any of several recent excellent reviews (23, 42, 124, 149).
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MAPKS, MKKS, AND MKKKS |
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The core MAPK "module" consists of a MAPK, its upstream
activator [MAPK kinase (MKK)], and a further upstream activator
[MAPK kinase kinase (MKKK); Fig.
1]. MAPKs can be divided into at
least three broad families on the basis of sequence
similarity, upstream activators, and to a lesser extent, substrate
specificity. The classic extracellular signal-regulated kinases (ERKs;
ERK1 and ERK2) were identified in the context of growth factor-related signaling, whereas the jun NH2-terminal kinase (JNK) and
p38 families were described in the setting of cell response to stress
and inflammation. Recently, additional MAPK families have been
identified, of which only ERK5 thus far has clearly delineated upstream
activators and downstream effectors (85, 173).
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Although the often-quoted paradigm of a discrete physical or biochemical stimulus (e.g, peptide mitogen, osmotic stress, etc.) resulting in activation of a specific MAPK module has been challenged by recent data, each family of MAPKs is nonetheless activated in a relatively specific fashion by a subset of MKKs (Fig. 1). For example, ERK1/2 is activated by both MAPK/ERK kinase (MEK)1 and MEK2 whereas JNKs are activated primarily by MKK4 and MKK7 and p38 is activated by MKK3 and MKK6. In contrast, the relationship between individual MKKs and their upstream MKKKs is less clear. Members of the Raf family specifically activate the ERK1/2-directed MKKs, MEK1, and MEK2, although there is considerable crosstalk among the parallel cascades at the level of MKKKs. Additional MKKK-MKK relationships are detailed in Fig. 1. A further level of complexity is contributed by the expanding range of activators of MKKKs (including MKKKKs and small GTP-binding proteins; reviewed in Ref. 42).
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THE ERK PATHWAY |
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The ERK1/2 pathway is generally but not exclusively responsive to activators of both receptor tyrosine kinases and G protein-coupled receptors. Principal mammalian ERKs, p44ERK1 and p42ERK2, are activated by the MEK1 and MEK2 "dual-specificity" (Ser/Thr and Tyr) kinases that phosphorylate the TEY motif specific to ERKs. Effectors of activated ERK include transcription factors [e.g., Elk-1, Ets 1, Sap1a, m-Myc, signal transducers and activators of transcription proteins (STAT)], adapter proteins (Sos), enzymes (p90Rsk S6 kinase, phospholipase A2), and cell surface and nuclear receptors [e.g., epidermal growth factor (EGF) and estrogen receptors, respectively]. Elucidation of physiological consequences of ERK signaling has been enormously facilitated by the availability of the pharmacological inhibitors of ERK action, PD-98059 (1) and, more recently, U-0126 (39). Both inhibitors appear to indirectly block ERK signaling through inhibition of its immediate upstream activators, MEK1 and MEK2. Specificity is not absolute; PD-98059 is also a potent inhibitor of cyclooxygenase-1 and -2 (15). A recently described highly MEK1-specific derivative of PD-98059, PD-184352, was functional in vivo, effectively suppressing tumor growth (128). From a physiological perspective, ERK signaling has been implicated in mitogenesis and cell differentiation. In vivo targeted gene disruption ("knockout") of ERK has not been reported, presumably due to embryonic lethality. Targeted gene disruption of the MKKK for the ERK and JNK pathways, MEKK1, enhanced the proapoptotic response to various stressors in embryonic stem cells (168); targeted disruption of MEKK2 has also been reported (167).
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THE JNK/SAPK1 PATHWAY |
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The JNK [also known as stress-activated protein kinase-1
(SAPK1)] family members are generally responsive to cell stressors such as hypertonicity, ultraviolet light, heat shock, and
proinflammatory cytokines. Members of this family include the widely
expressed JNK1 (also known as p46 or SAPK1) and JNK2 (also known as
p54 or SAPK1
), as well as the brain-specific JNK3 (also known as p49
or SAPK1
). JNK1 and JNK2 are subject to alternative splicing, giving
rise to 46- and 54-kDa protein products. To achieve activation, JNKs
undergo MKK-mediated dual phosphorylation at their TPY motifs. Effectors of the JNK family of MAPKs include primarily transcription factors (e.g., c-Jun, Elk-1, ATF-2, DPC4, NFAT4, and p53). Although no
pharamacological inhibitor of the JNK pathway has been widely used, the
activator protein-1 (AP-1) and nuclear factor-
B inhibitor curcumin
(20) and the quinone reductase inhibitors dicoumarol and
menadione (27) specifically blocked JNK activation and
JNK-dependent signaling in diverse contexts through unknown mechanisms.
JNKs in vivo appear to play a role in inflammation, tumorigenesis, and
apoptosis; independent targeted disruption of JNK1, JNK2, and JNK3 have
been reported and are viable (36, 160, 161). Recently, a
JNK1/JNK2 double knockout conferred embryonic lethality and exhibited
dysregulated apoptosis in the central nervous system (90).
Disruption of MKK4, a JNK-directed MKK, also resulted in embryonic
lethality, at least in part, through abnormal hepatogenesis (41,
113, 159).
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THE P38/SAPK2 PATHWAY |
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The p38 (also known as SAPK2) family includes four isozymes ( through
), subject to dual phosphorylation at the TGY motif, primarily by the MKKs, MKK3, and MKK6. Members of the p38 family, like
the JNK family, are generally but not exclusively responsive to
environmental stressors. Effectors of the p38 family include both
transcription factors (ATF-2, Elk-1, CHOP/Gadd153, Max, MEF2C) and
enzymes (e.g., MAPKAP kinase). Implication of p38 signaling in cell
physiology was facilitated by the identification of a family of
anti-inflammatory pyridinyl imidazole compounds, including SB-203580
(100), that inhibit most (but not all) p38 isozymes with
high specificity (84). Like PD-98059, however, SB-203580 also inhibits cyclooxygenase-1 and -2, as well as thromboxane synthase
(15). Although targeted disruption of p38 isoforms in vivo
has not been reported, knockout of its immediate upstream activator,
MKK3, exhibited dysregulated cytokine production in vivo (103,
154).
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SPECIFICITY IN MAPK SIGNALING CASCADES |
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Although crosstalk is evident among parallel MAPK modules, paradigms are beginning to emerge. Much confusion arose from earlier reliance on overexpression of components of MAPK cascades and in vitro demonstration of substrate phosphorylation. The greatest degree of specificity (i.e., least crosstalk) in MAPK signaling now appears to reside at the level of MKK activation of MAPK (Fig. 1). Substrate activation by MAPKs, in contrast, is a site of conspicuous crosstalk. For example, the transcription factor Elk-1 may be activated by members of each of the three principal MAPK families, whereas other substrates appear to be activated in a highly MAPK-specific fashion. Upstream activation events (mediated by MKKKs and recently identified MKKKKs) comprise another incompletely understood locus of integrative crosstalk. Additional variables conferring greater specificity to MAPK-mediated substrate phosphorylation likely include cell type-specific distribution of MAPK-activating cell surface receptors, timing and duration of MAPK activation (e.g., 104, 119), involvement of single vs. multiple MAPK modules, and convergence of other signaling events on individual MAPK cascades (e.g., 143). In this respect, it is important to emphasize that physiological stimuli at the organismic level (e.g., inflammation or hypotension) have numerous biochemical effectors and that the local end organ-specific consequences of such stimuli, in terms of posttranslational modification and transcriptional regulation, will likely represent the net effect of myriad qualitative and quantitative changes in intracellular signaling inputs.
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REGULATION BY COLOCALIZATION |
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Although alternative splice products among JNK isoforms have been noted with interest for several years and represent an attractive candidate for a higher order of MAPK regulation, data in support of this model are lacking. Evidence supporting other higher orders of MAPK regulation, in contrast, is mounting. The issue of relative lack of specificity of MAPK, MKK, and MKKK in vitro catalyzed a search for proteins that might permit separate elements of a MAPK module to colocalize in vivo and thereby confer both greater efficiency of activation and enhanced specificity. Such scaffolding proteins have now been identified for ERK (123) and JNK (14, 32, 148) in higher eukaryotes, and for the yeast high osmolority glycerol 1 (HOG1) pathway, homologous with the mammalian p38 pathway. MEKK1, a MKKK for the ERK and JNK pathways, may itself function as a scaffolding protein for MKK4 and JNK (156, 158).
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REGULATION BY MAPK-DIRECTED PHOSPHATASE ACTIVITY |
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In addition to positive regulation by MKK-mediated phosphorylation, MAPKs are also subject to negative regulation through dephosphorylation. At least nine distinct dual-specificity (TXY-directed) phosphatases have been described (55) that antagonize MKK function. The first characterized in detail, MKP-1 (also known as hVH1, 3CH143, and CL100), is a nuclear protein and immediate-early gene product exhibiting equivalent phosphatase activity against ERK, JNK, and p38 MAPKs (55). Other MAPK-directed phosphatases, in contrast, exhibit marked substrate specificity; the phosphatase MKP-3, for example, is most active against phosphorylated ERK (46, 111). Interestingly, association of MKP-3 with ERK dramatically enhanced its intrinsic ERK-directed phosphatase activity (17).
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IN VIVO MODELS OF RENAL MAPK ACTIVATION |
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Although all three principal MAPKs are expressed in whole kidney and detectable in various renal cell culture models (see below), relatively little is known about renal cell type-specific expression patterns of MAPKs and their activators and effectors in vivo. Terada et al. (138) showed that ERK1 and ERK2 are expressed in all nephron segments, as is the MKKK, Raf-1, the MKK, MEK, and the ERK effector, p90 S6 kinase (Rsk).
In vivo renal model systems have primarily included models of inflammatory, ischemic, or toxic renal injury, or extreme physiological stress. Two rodent models of proliferative anti-glomerular basement membrane glomerulonephritis were associated with increased renal cortical and glomerular ERK and JNK activation (11). At least a component of the activated ERK was likely contributed by infiltrating macrophages on the basis of depletion studies using total-body X-irradiation (11). Interestingly, these models were also associated with upregulation of the ERK activator, MEK, at the mRNA level. A model of primarily mesangial proliferative glomerulonephritis inducible by anti-thymocyte serum (ATS) was similarly associated with activation of ERK, p38, and JNK MAPKs in renal tissue (12, 13, 129). Prednisolone therapy, which improved proteinuria and glomerular hypercellularity in this model, also blocked the ATS-mediated increment in ERK and JNK activation (129). Therapy with heparin similarly abrogated ERK activation and the concomitant glomerular proliferation (13). Pretreatment with phosphodiesterase inhibitors known to interfere with the ERK pathway (105) ameliorated the clinical severity of ATS-associated renal failure (141), but data with respect to MAPK activation are lacking in this experimental model. The beneficial effect of phosphodiesterase inhibitors appeared to be independent of their modest protective effect on blood pressure (141). The significance of these latter data with respect to blood pressure are underscored by the recent observation that subacute glomerular injury induced by salt loading in the Dahl salt-sensitive rat is associated with chronic activation of glomerular ERK and JNK (50). In contrast to these animal models, data addressing the role of MAPK activation in human proliferative glomerular disease are sparse. In one small series, the activity of phospholipase A2, an effector of activated ERKs, was increased in the urine of patients with mesangial proliferative glomerulonephritis (134).
Rodent models of renal ischemia-reperfusion were associated with renal JNK (33, 118) and p38 (165), but not ERK (118), activation, as well as activation (enhanced DNA binding) of the MAPK-responsive transcription factors, c-Jun and ATF-2 (110). Recently, a potentially novel JNK isoform was identified in this clinically relevant context (31). The profile of MAPK activated by ischemia-reperfusion may be somewhat tissue specific (165). From a therapeutic perspective, the ischemia-associated activation of JNK may be ameliorated by systemic administration of the thiol-containing antioxidant N-acetylcysteine (33).
Toxic renal injury experimentally induced by mercuric chloride administration, curiously, was associated with two temporal peaks of renal ERK activation, separated by an interval of relative inactivity (163). Renal ERK and JNK activation were also increased in the glycerol model of myoglobinuric acute renal injury (80). Interestingly, this latter effect was modestly sensitive to systemic administration of the relatively nonspecific kinase inhibitor genistein (80).
An increased incidence of ERK activation has been observed in human renal neoplasia. Oka et al. (114) noted constitutive ERK activation in fully 48% of renal carcinomata examined (114). Hoshino et al. (58) detected ERK activation in tumors derived from diverse tissues; however, a disproportionate incidence was noted in tumors arising from the kidney.
With respect to physical stressors, exogenously applied heat stress increased JNK activation in mouse kidney, as well as other (but not all) tissues (60). Osmotic stress regulates all MAPKs in cell culture models (see below); accordingly, physiological models of systemic water balance profoundly influence renal medullary MAPK activation. Water restriction increased ERK, p38, and JNK activity in renal medullary but not cortical tissue (151, 166). Therefore, despite the markedly elevated medullary tonicity under euvolemic conditions, MAPK activation is submaximal in this unique environment. The relationship between hypertonicity and experimental models of hyperglycemia and diabetes mellitus is often unclear. ERK activity is increased in glomeruli harvested from diabetic animals; similarly, exogenous application of elevated glucose to isolated glomeruli activated ERK (7, 52, 53).
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CELL CULTURE MODELS OF MAPK ACTIVATION |
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Mesangial Cells
The principal in vitro (cell culture) model systems of renal MAPK regulation are the mesangial and tubular epithelial cell. Because ERK activation is often a manifestation of mitogenesis and because mesangial cell proliferation is a hallmark of numerous glomerular lesions, intense interest has focused on MAPK regulation in mesangial cells. Abundant agonists capable of activating MAPKs in cultured mesangial cells have been described, including peptide mitogens, cytokines, lipid mediators, and steroid hormones, and physical stimuli potentially relevant to mesangial function in vivo (Table 1). ERKs are activated by the peptide mitogen and receptor tyrosine kinase agonists, platelet-derived growth factor (PDGF) (22, 67, 73, 125), EGF (125), insulin (3), and vascular endothelial growth factor (VEGF) (2), as well as the G protein-coupled-receptor-directed agonists endothelin (88, 125, 144, 145), ANG II (3, 67), bradykinin (38, 83), lysophosphatidic acid (40, 73), serotinin (45), and vasopressin (78, 79, 95). The effect of vasopressin on mesangial ERK activation is likely Ras dependent, as evidenced by its sensitivity to the hydroxymethylglutaryl-CoA inhibitor (and, therefore, prenylation inhibitor) simvastatin (78). The effect of lysophosphatidic acid in this model likely requires activation of the PDGF receptor (44). Activation of the G protein-coupled purinergic receptor by nucleotide triphosphates also induces ERK activation (65, 76) and is sensitive to the antioxidant N-acetylcysteine (65). In addition to ERK, several agonists of G protein-coupled receptors also activate JNK in mesangial cells, including ANG II (69), endothelin (4), and nucleotide triphosphates (70).
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As in other models, proinflammatory cytokines such as tumor necrosis
factor- (49) and interleukin-1
(IL-1
) (63,
134, 142, 150) activate various MAPKs in glomerular mesangial
cells in culture, an effect that may be dependent on the generation of
oxidative stress (150). Activation of JNK in this context may also require arachidonic acid release (61), whereas
activation of both p38 and JNK appears to mediate the ability of
inflammatory cytokines to upregulate expression of cyclooxygenase-2
(47). Similarly, p38 and/or JNK activation is likely
required for IL-1-inducible chemoattractant protein-1
(122) and nitric oxide synthase expression (48). The cytokine transforming growth factor-
2 also
activates ERK in mesangial cells (66), whereas nitric
oxide activates all three MAPK families (16, 64, 117).
The lipid mediators lysophosphatidic acid (40, 73) and sphingosine (26) as well as selected lipoproteins (8, 109) all induce ERK activation in cultured mesangial cells. In addition, ERK and p38 appear to play a role in gene regulation downstream of lysophosphatidic acid signaling (120) in this model. Interestingly, whereas the lipid mediator ceramide activates JNK but not ERK, the ceramide metabolite sphingosine specifically activates ERK but not JNK (26). Correspondingly, ceramide generation has been implicated in cytokine signaling and sphingosine production in the growth factor response. Low-density lipoprotein can potentiate the effect of vasopressin on ERK activation (77). Exogenous application of soluble phospholipase A2, catalyzing the enzymatic release of free arachidonic acid from biological membranes, activated ERK in mesangial cells (68, 134). Phospholipase A2 is also activated by ERK, suggesting the interesting scenario of cyclic potentiation of ERK signaling in this specific context.
Physical stimuli such as hyperglycemia (43, 52-54, 56), cyclic two-dimensional mechanical stretch and relaxation (72, 74), and collagen gel three-dimensional contraction (169) all activate ERK in mesangial cells. Elevated hydrostatic pressure is particularly relevant to the mesangium in vivo; an in vitro model achieved by using an air pressure loading apparatus (to 70 mmHg) resulted in enhanced mesangial cell ERK activation and proliferation (86). A measure of specificity in these events is implied by the inability of elevated pressure to activate JNK (86), and the additional ability of mechanical strain to activate p38 but not JNK (72). Cadmium induces ERK activation (136, 146), but it is unclear whether this represents a heavy metal (toxic) or oxidative stress-dependent effect.
In addition to activators, several stimuli functionally antagonize MAPK signaling in the mesangial cell model. With respect to ERK signaling, vasodilatory mediators such as prostaglandin analogs (71, 102), dopamine (164), atrial natriuretic peptide (51, 133), and adrenomedullin (21, 116) all block ERK activation in various contexts, as do heparin (108), high glucose (106), phosphodiesterase inhibitors (105), and cAMP and cGMP analogs (51, 132). A number of these inhibitory events appear to be mediated through the action of cyclic nucleotide monophosphate (e.g., cAMP and cGMP) second-messenger systems.
In addition to regulating activation of MAPKs, several stimuli may
directly regulate abundance of MAPK cascade consituents. For example,
in addition to increasing ERK activity, transforming growth factor-2
(66), IL-1 (63), endothelin-1 (126,
127), PDGF (126, 127), and fetal bovine serum
(126) also increased the abundance of mRNA coding for the
ERK activator MEK in mesangial cells. Similarly, in addition to
activating ERK, PDGF stimulates ERK synthesis (62). A
prostacyclin analog increases expression of the ERK-directed
phosphatase MKP-1 and thereby potentially antagonizes MAPK signaling in
the mesangium (140).
Renal Tubular Epithelial Cells
A subset of renal epithelial cells lining the distal nephron are subjected to an elevated and, at times, rapidly fluctuating ambient osmolarity as a consequence of the renal concentrating mechanism. In light of earlier descriptions of activation of each of the three prinicpal MAPK families by hypertonic stress, the renal epithelial cell (and particularly, renal medullary cell) model provided an ideal physiological context in which to explore this phenomenon. Several recent reviews (92, 98) address this theme in greater detail. As in other (nonrenal) models, application of hypertonicity to renal epithelial cells in culture activates ERK (82, 137), p38 (10, 147, 170), and JNK (10, 170) (See Table 2). Hypotonicity also increases activation of ERK and JNK in this model (172), events that partially explain the ability of this stimulus to activate immediate-early gene expression. Although pharmacological inhibition of the ERK pathway affected cell volume regulation, it did not appear to influence cell viability in the setting of hypotonicity (172). The role of each of these kinases in gene regulation by hypertonicity is less clear. Kwon et al. (96) reported that ERK activation in Madin-Darby canine kidney (MDCK) cells was dispensible for osmotic induction of genes encoding osmolyte transporters (96). Kultz et al. (93) reported that, in the renal medullary mIMCD3 cell line, tonicity-inducible transcription directed by the osmotic or tonicity-responsive DNA enhancer element was similarly independent of p38 activation and that heterologous overexpression of dominant negative MKK3 and MKK4 isoforms failed to influence osmotic gene induction. Sheikh-Hamad et al. (130), in sharp contrast, observed that pharmacological inhibition of p38 action blocked hypertonicity-inducible transcription of genes encoding both the heat shock protein HSP70 and osmolyte transporters. In terms of cell volume regulation, p38 activation likely mediates a component of the regulatory volume increase response in cells of the medullary thick limb (121). Activation of p38 has also been reputed to mediate, in part, the ability of hypertonicity to increase expression of the stress-responsive protein products of the GADD45 and GADD153 genes (94). With respect to the JNK pathway, Wojtaszek et al. (152) observed that hypertonicity activated JNK2 but not JNK1 in the mIMCD3 model; more importantly, inhibition of the JNK2 pathway through a dominant negative approach sensitized cells to the proapoptotic effect of hypertonicity. In addition to regulating MAPK activation, anisotonicity also influences abundance of a MAPK antagonist. Specifically, expression of the ERK-directed phosphatase MKP-1 is responsive to ambient tonicity in the MDCK model (81), affording an additional level of complexity.
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Similar in some respects to hypertonic stress is the unique medullary stress engendered by urea. Urea, in concentrations unique to the renal medulla, activates primarily the ERK MAPKs (10, 24, 170) in inner medullary collecting duct cells, although modest activation of JNK and p38 has also been observed in this model (10, 162). Urea-inducible ERK activation, a partially Ras-dependent phenomenon (139), results in activation of the translational regulatory kinase p90Rsk (171) and underlies, in part, the ability of this stimulus to regulate immediate-early gene transcription (24). The medullary cell response to urea is distinct from that of hypertonicity in a number of respects, and is in large part cell volume independent (162)
As in other models, receptor agonists regulate activation of MAPK
family members in renal tubular epithelial cells. With respect to
receptor tyrosine kinase activators, EGF activated ERK in IMCD and OMCD
cells (57, 138). Hepatocyte growth factor activated ERK in
the MDCK cell line (135), a signaling event implicated in
hepatocyte growth factor-inducible epithelial cell scatter (135). With respect to G protein-coupled receptor
agonists, bradykinin activated ERK in cortical collecting duct cells
(97), purinergic agonists (NTPs) activated ERK in MDCK and
inner medullary collecting duct (IMCD)/T cells (57, 75,
155), ANG II activated ERK in opossum kidney (OK) proximal
tubule-like and IMCD cells (137), epinephrine activated
ERK in MDCK cells (155), endothelin activated ERK in IMCD
and outer medullary collecting duct cells (138), G1-2 activated ERK in LLC-PK1 cells
(87), and carbachol activated ERK in inner medullary
collecting tubule cells (57). Bradykinin induces
arachidonic acid release via ERK activation (97), an event
potentially attributable to downstream activation of phospholipase
A2. Other ERK activators in renal epithelial models include
lactosylceramide, a lipid mediator increased in polycystic kidney
disease tissue that increased ERK activity in human tubular epithelial
cells (18); arachidonic acid, which increased ERK activity
in rabbit proximal tubule cells (37); epoxyeicosatrienoic
acid, lipid signaling intermediates that increased ERK activity in
LLC-PKc14 cells (19); advanced glycation
end-products, nonenzymatically modified macromolecules associated with
hyperglycemia and diabetes mellitus that increased ERK activity in
LLC-PK1 cells (131); and ATP depletion, which
also activated ERK in the LLC-PK1 model (110).
Only very limited data describe nonosmotic regulation of MAPKs other than ERKs in renal tubular epithelial models. The heavy metal and oxidative stressor cadmium activated JNK in LLC-PK1 cells (107), consistent with data in other models. JNK was also activated in rabbit proximal tubule cells in response to arachidonic acid treatment, an effect dependent on NADPH oxidase activity (28).
Antagonists of MAPK (specifically, ERK) in renal epithelial cells, as in mesangial cells, likely function in a cAMP-dependent fashion. For example, vasopressin inhibited EGF-inducible ERK activation in MDCK cells (157). Nonenzymatically glycated extracellular matrix, accompanying diabetes mellitus in vivo, also has been shown to block activation of ERK (89), in marked contrast to the effect of exogenously applied advanced glycation end-products described above (131). Also of note with respect to renal pathophysiology, the protein product of the VHL locus, implicated in renal carcinoma development, appears to interfere with ERK activation (115). The relationship between this biochemical finding and the pathogenesis of neoplasia remains speculative, however.
Other Glomerular Cell Types
In contrast to mesangial cells and renal tubular epithelial cell types, less is known about MAPK regulation in other resident renal cells. In glomerular epithelial cells, the likely origin for crescent formation in inflammatory glomerulopathies, exogenous application of complement-activated ERK and the ERK effector phospholipase A2 but not p38 (30). ERK activation in this model may also be modulated in part by matrix composition (29). In glomerular endothelial cells, in direct contact with the intraglomerular bloodspace in vivo, the vasoactive mediators ANG II and nitric oxide activated both ERK (153) and JNK (117), respectively. Although performed in the relatively poorly differentiated human embryonal HEK-293 kidney cell line, recent studies addressing signaling events engendered by the protein products of the polycystic kidney disease loci are of great interest. Specifically, heterologous overexpression of PKD1 resulted in activation of JNK but not ERK or p38 (5) and further led to enhanced AP-1-dependent (i.e., immediate-early gene) transcription. In contrast, heterologous overexpression of PKD2 resulted in activation of both JNK and p38. Like overexpression of PKD1, PKD2 expression was associated with enhanced AP-1-dependent transcription (6); however, coexpression of these protein products markedly augmented signaling to AP-1-dependent transcription. ![]() |
SUMMARY AND FUTURE DIRECTIONS |
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In renal cells in culture, a broad range of biochemical, pharmacological, and even physical stimuli all converge on activation of elements of one or more of the MAPK families. Comparatively few such events have been observed in in vivo models of renal pathophysiology; far fewer still have been directly implicated in human renal disease, owing in large part to the paucity of clinical material and the extreme lability of the activation (phosphorylation) events under investigation. It is anticipated that elucidation of downstream effector signaling mechanisms and a clearer understanding of immediate and remote upstream activating pathways, when applied to these disparate but highly clinically relevant renal cell culture model systems, will ultimately provide much greater insight into the basis for specificity now seemingly absent from these signaling events. An appreciation of this specificity, or lack thereof, is a prerequisite for the intelligent application of pharmacological interventions aimed at disrupting or potentiating these signaling pathways in combating human disease.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-52494 and by the American Heart Association.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. M. Cohen, Oregon Health Sciences Univ., Portland, OR 97201 (E-mail:cohend{at}ohsu.edu).
1 The following search algorithm (PubMed) was used (through 2/00): (ERK OR extracellular-signal OR MAPK OR mitogen-activated OR SAPK OR stress-activated OR JNK OR c-jun NH2-terminal OR jun N-terminal OR p38 OR HOG1) AND (renal OR kidney OR nephron OR glomerular OR glomerulus OR mesangial OR mesangium).
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