The renal nerve is required for regulation of proximal tubule transport by intraluminally produced ANG II

Albert Quan1 and Michel Baum1,2

Departments of 1 Pediatrics and 2 Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9063


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The proximal tubule synthesizes and luminally secretes high levels of angiotensin II, which modulate proximal tubule transport independently of systemic angiotensin II. The purpose of this in vivo microperfusion study is to examine whether the renal nerves modulate the effect of intraluminal angiotensin II on proximal tubule transport. The decrement in volume reabsorption after addition of 10-4 M luminal enalaprilat is a measure of the role of luminal angiotensin II on transport. Acute denervation decreased volume reabsorption (2.97 ± 0.14 vs. 1.30 ± 0.21 nl · mm-1 · min-1, P < 0.001). Although luminal 10-4 M enalaprilat decreased volume reabsorption in controls (2.97 ± 0.14 vs. 1.61 ± 0.26 nl · mm-1 · min-1, P < 0.001), it did not after acute denervation (1.30 ± 0.21 vs. 1.55 ± 0.19 nl · mm-1 · min-1). After chronic denervation, volume reabsorption was unchanged from sham controls (2.26 ± 0.28 vs. 2.70 ± 0.19 nl · mm-1 · min-1). Addition of luminal 10-4 M enalaprilat decreased volume reabsorption in sham control (2.70 ± 0.19 vs. 1.60 ± 0.10 nl · mm-1 · min-1, P < 0.05) but not with chronic denervation (2.26 ± 0.28 vs. 2.07 ± 0.20 nl · mm-1 · min-1). Addition of 10-8 M angiotensin II to the lumen does not affect transport due to the presence of luminal angiotensin II. However, addition of 10-8 M angiotensin II to the tubular lumen increased the volume reabsorption after both acute (1.30 ± 0.21 vs. 2.67 ± 0.18 nl · mm-1 · min-1, P < 0.05) and chronic denervation (2.26 ± 0.28 vs. 3.57 ± 0.44 nl · mm-1 · min-1, P < 0.01). These data indicate that renal denervation abolished the luminal enalaprilat-sensitive component of proximal tubule transport, which is consistent with the renal nerves playing a role in the modulation of the intraluminal angiotensin II mediated component of proximal tubule transport.

volume reabsorption; renal denervation; renin-angiotensin system


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE SYMPATHETIC RENAL NERVES richly innervate the proximal tubule and play an important role in the regulation of proximal tubule sodium reabsorption (1, 9, 10, 21). Stimulation of the renal nerves augments proximal tubule sodium reabsorption, whereas renal denervation decreases proximal tubule sodium reabsorption (3-5, 10). These effects occur independently of changes in the glomerular filtration rate, renal blood flow, and peritubular Starling forces and indicate that the renal nerves directly modulate proximal tubule transport (3-5, 10).

The stimulatory effect of the renal nerves on proximal tubule transport has been shown to be affected by systemic angiotensin II, a circulating hormone that also plays a regulatory role in proximal tubule transport (11, 14, 15). When circulating angiotensin II levels are decreased with saline loading or administration of DOCA or captopril, the increase in renal sodium reabsorption induced by renal nerve stimulation is markedly diminished (14). However, when angiotensin II levels are restored by systemic infusion at physiological levels that do not alter blood pressure, subsequent renal nerve stimulation augmented sodium reabsorption by the proximal tubule (14). These studies indicate that the renal nerves interact with the systemic renin-angiotensin system to regulate proximal tubule transport.

In addition to the systemic renin-angiotensin system, the proximal tubule also contains an autonomous renin-angiotensin system whereby angiotensin II is locally produced and luminally secreted at levels 100-fold greater than in plasma (7, 13, 20, 23, 27, 29, 30). This proximal tubule renin-angiotensin system has been shown to modulate proximal tubule transport independently of systemically circulating angiotensin II (2, 12, 16, 18, 24-26). Inhibition of luminal angiotensin II production within the proximal tubule with administration of luminal enalaprilat decreases proximal tubule volume reabsorption (24). A comparable reduction in proximal tubule volume reabsorption was also observed with luminal administration of losartan, a type 1 angiotensin II (AT1)-receptor antagonist (2, 24). These studies demonstrate that the proximal tubule renin-angiotensin system through luminal angiotensin II can modulate proximal tubule transport independently of systemically circulating angiotensin II.

Unexplored to date, however, is the potential role of the renal nerves to interact with the proximal tubule renin-angiotensin system. The regulation of the renal nerve's effect on proximal tubule transport by the systemic renin-angiotensin system poses an intriguing possibility that a similar interaction between the renal nerves and the proximal tubule renin-angiotensin system might exist. In this study, we examine whether the renal nerves can modulate the effect of proximal tubule luminal angiotensin on volume transport.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Preparation of animals. Male Sprague-Dawley rats, weighing between 190 and 250 g, were used for this study. Rat preparation and in vivo microperfusion have been described previously (24, 26). Briefly, all animals were allowed free access to food and water before anesthesia with intraperitoneal inactin (100 mg/kg). Rats were placed on a servo-controlled heated table set to maintain body temperature at 37°C. A tracheostomy was performed, and the jugular vein was cannulated for infusion of normal saline at 2.8 ml/h. A flank incision was then used to expose the left kidney, which was then immobilized in a lucite cup. The kidney was bathed with water-equilibrated mineral oil heated to 37°C that was previously bubbled with 95% O2-5% CO2. The ureter was cannulated with polyethylene tubing (PE-50) to ensure free flow of urine.

In vivo microperfusion. Proximal tubule segments on the surface of the kidney were initially mapped with injection of a small droplet of oil. A wax block was inserted into the lumen of an early proximal tubule loop by a hydraulic Microdrive (Trent Wells, Coulterville, CA), which prevented any glomerular filtrate from flowing into the tubule segments distal to the block. Subsequently, a microperfusion pipette was inserted into the lumen immediately distal to the wax block, and tubules were perfused (30 nl/min) with a microperfusion pump system (K. Effenberger, Vestavia Scientific, Birmingham, AL). Tubules were perfused with an ultrafiltrate-like solution, which was composed of (in mM) 120 NaCl, 25 NaHCO3, 5 KCl, 1 MgSO4, 1.8 CaCl2, 1 Na2HPO4, 5 glucose, 5 alanine, and 5 urea, as well as 0.1% FD & C green dye no. 3. Exhaustively dialyzed [3H]methoxy inulin was added as a volume marker. In a late proximal tubule loop distal to the perfusion pipette an oil block was placed, and a collection pipette was then inserted proximal to the oil block. An average of three tubules were perfused per kidney. Fluid collections were made over a 2- to 3-min period, and the volume was measured by using a constant-bore pipette. Only perfused tubules with an inulin recovery rate of >90 and <110% were included (actual, >90 to <105%). After all collections were performed, the entire tubule was injected with liquid microfil (Flow-Tech, Carver, MA) and allowed to harden overnight. The kidney was later placed in 6 N HCl at 37°C for 1 h. The microfil tubule casts were then dissected and photographed, and the tubular length between the perfusion and collection sites was measured. Microfil dissection and calculation of the rate of volume absorption (Jv) were performed without knowledge of the specific experimental protocol.

Acute and chronic renal denervation. Acute renal denervation was accomplished by the standard mechanicochemical technique after the ureter had been cannulated (3, 31, 32). Briefly, the renal arterial adventitia was stripped, and 10% phenol in absolute ethanol was applied circumferentially around the vessel for 15-20 min. Care was taken to prevent contact of phenol with other surrounding structures. If vasospasm of the renal artery was noted, the animal was not used for the study.

In rats used for the chronic renal denervation studies, denervation of the renal nerves was performed 6-7 days before in vivo microperfusion (31, 32). Using this denervation technique, we demonstrated a 90% reduction in whole kidney norepinephrine content 6 days after surgery [27.2 ± 15.8 vs. 214.7 ± 44.8 pg/mg (contralateral nondenervated kidney), P < 0.005] and [27.2 ± 15.8 vs. 282.7 ± 48.4 pg/mg (sham nondenervated kidney), P < 0.005], respectively. Whole kidney norepinephrine was measured by using a catecholamine research assay system (catecholamines [3H] radioenzymatic assay, Amersham Pharmacia Biotech). Briefly, the kidney was homogenized in 0.4 N perchloric acid, subjected to the enzyme, catechol-O-methyltransferase, and the resulting [3H]methoxy-labeled catecholamine derivative was isolated by thin-layer chromatography and measured by scintillation counting. As a control for the chronically denervated animals, sham animals received a comparable operation except that renal denervation did not take place.

Animal protocols. The role of intraluminally produced angiotensin II on proximal tubule transport was studied in four groups of animals: control, acutely denervated animals, chronically denervated animals, and sham-operated control animals. Four or more animals were used within each of the study groups. Proximal tubules were perfused with an ultrafiltrate-like solution, and the rate of proximal tubule volume reabsorption was measured. To determine the role of intraluminally generated angiotensin II on proximal tubule transport, proximal tubule volume reabsorption was also measured in the presence of 10-4 M luminal enalaprilat to inhibit intraluminal angiotensin II production. Luminal 10-4 M enalaprilat has previously been shown to decrease proximal tubule volume reabsorption by 40% (24). The difference in volume reabsorption observed between tubules perfused with and without 10-4 M enalaprilat is a measure of the contribution of intraluminally generated angiotensin II on proximal tubule transport (2, 24-26). Finally, proximal tubules in acutely and chronically denervated animals were perfused with an ultrafiltrate-like solution containing 10-8 M angiotensin II to determine effect of luminal angiotensin II on proximal tubule transport in denervated kidneys. The concentration of angiotensin II within the luminal fluid of the proximal tubule has previously been measured and found to be 10-8 M (7, 23).

Mean arterial blood pressure was not different in control (100-110 mmHg), acutely denervated (97-105 mmHg), or chronically denervated animals (100-109 mmHg) (Table 1). Blood pressure was measured with a femoral artery catheter connected to a calibrated pressure transducer (Ohmeda, Madison, WI) with a digital readout (Columbus Instruments, Columbus, OH). The glomerular filtration rate of the single kidney to be studied was measured in control, acutely denervated, and chronically denervated animals (n = 4). There were no statistical differences in the glomerular filtration rates among all three groups: 4.24 ± 0.28 (control), 4.45 ± 0.18 (acutely denervated kidney), and 4.75 ± 0.29 ml · min-1 · kg-1 (chronically denervated kidney) (Table 1).

                              
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Table 1.   Hemodynamics of DNX rats

Calculations and statistical analyses. The proximal tubule volume reabsorptive rate (Jv) was calculated in accordance to the following equation
J<SUB>V</SUB><IT>=</IT><FR><NU><IT>V<SUB>0</SUB>−V<SUB>L</SUB></IT></NU><DE><IT>l</IT></DE></FR>
where, V0 is the calculated perfusion rate (nl/min), VL is the measured collection rate (nl/min), and l is the length (in mm) of the perfused proximal tubule. V0 was obtained by measuring the radioactivity of the collected tubular fluid (TF) in counts per minute per nanoliter and the perfused ultrafiltrate-like solution (P) in counts per minute per nanoliter and by using the following equation
V<SUB>0</SUB>=<FR><NU>TF</NU><DE>P</DE></FR><IT>×V<SUB>L</SUB></IT>
Statistical analyses were performed with one-way ANOVA with a Student-Newman-Keuls multiple-comparisons test. Statistically significant data were determined with a P value < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of chronic renal denervation on the role of intraluminally generated angiotensin II on proximal tubule volume reabsorption. In these studies the role of intraluminal angiotensin II on proximal tubule volume reabsorption was examined in Sprague-Dawley rats 6-7 days after renal denervation or sham operation. Chronic renal denervation did not significantly reduce the rate of proximal tubule volume reabsorption compared with the sham control. Proximal tubules from sham-operated animals had a volume reabsorption rate of 2.70 ± 0.19 nl · mm-1 · min-1, which was significantly greater than 1.60 ± 0.10 nl · mm-1 · min-1 measured in proximal tubules perfused with an ultrafiltrate-like solution containing 10-4 M luminal enalaprilat (P < 0.05, Fig. 1). Luminal enalaprilat (10-4 M) has previously been shown to inhibit proximal tubule volume reabsorption by 40% (24). However, in chronically denervated tubules the rate of volume reabsorption was 2.26 ± 0.28 nl · mm-1 · min-1, which was not different from the 2.07 ± 0.20 nl · mm-1 · min-1 measured in the presence of 10-4 M luminal enalaprilat (Fig. 2).


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Fig. 1.   Proximal tubule volume reabsorptive rate (Jv) with ultrafiltrate-like perfusate, and ultrafiltrate-like perfusate plus 10-4 M enalaprilat in sham control rats. n, No. of proximal tubules perfused. *P < 0.05 vs. control.



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Fig. 2.   Proximal tubule Jv in chronically denervated (DNX) rats with ultrafiltrate-like perfusate, ultrafiltrate-like perfusate plus 10-4 M enalaprilat, and ultrafiltrate-like perfusate plus 10-8 M angiotensin II. Addition of 10-8 M angiotensin II augmented Jv, whereas 10-4 M enalaprilat failed to decrease Jv. n, No. of proximal tubules perfused. *P < 0.01 vs. chronic DNX. #P < 0.001 vs. chronic DNX+10-4 M enalaprilat.

We have previously shown that addition of 10-8 M luminal angiotensin II to the proximal tubule of innervated kidneys had no effect on the rate of volume reabsorption (2.95 ± 0.37 vs. 2.55 ± 0.32 nl · mm-1 · min-1), likely due to the high levels of luminal angiotensin II secreted into the proximal tubular lumen (7, 23, 24, 29). We next examined whether addition of exogenous angiotensin II to the luminal perfusate would increase volume reabsorption in proximal tubules from chronically denervated kidneys. The luminal angiotensin II concentration has previously been shown to be in the range of 0.5-4 × 10-8 M (7, 23, 29). As seen in Fig. 2, the addition of 10-8 M angiotensin II to the luminal perfusate resulted in a rate of volume absorption of 3.57 ± 0.44 nl · mm-1 · min-1, which was significantly higher than in tubules from denervated rats perfused with an ultrafiltrate-like solution without luminal angiotensin II (2.26 ± 0.28 nl · mm-1 · min-1, P < 0.01). These results are consistent with a decrease effect of intraluminal angiotenisn II on proximal tubule volume transport after chronic renal denervation.

Effect of acute renal denervation on intraluminally generated angiotensin II mediated proximal tubule transport. We next studied the effect of acute renal denervation on proximal tubule volume reabsorption. As seen in Fig. 3, the rate of proximal tubule volume reabsorption was significantly less in proximal tubules from acutely denervated kidneys than proximal tubules from kidneys with intact innervation (1.30 ± 0.21 vs. 2.97 ± 0.14 nl · mm-1 · min-1, P < 0.001). In tubules with intact renal innervation, the rate of volume reabsorption was significantly lower in the presence of 10-4 M luminal enalaprilat (1.61 ± 0.26 nl · mm-1 · min-1) compared with control innervated tubules perfused with an ultrafiltrate-like solution (2.97 ± 0.14 nl · mm-1 · min-1, P < 0.001, Fig. 3). This is consistent with our previous findings that addition of a converting enzyme inhibitor to decrease intraluminally generated proximal tubule angiotensin II production reduces the rate of proximal tubule transport (2, 24-26).


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Fig. 3.   Proximal tubule Jv with ultrafiltrate-like perfusate, ultrafiltrate-like perfusate plus 10-4 M enalaprilat, and ultrafiltrate-like perfusate in acutely DNX rats. Jv was lower than control with 10-4 M enalaprilat and with acute denervation. n, No. of proximal tubules perfused.*P < 0.001 vs. control.

The effect of luminal 10-4 M enalaprilat on proximal tubule volume reabsorption in proximal tubules from acutely denervated tubules is shown in Fig. 4. The rate of proximal tubule volume reabsorption in denervated kidneys was 1.30 ± 0.21 nl · mm-1 · min-1 and was unchanged compared with 1.55 ± 0.19 nl · mm-1 · min-1 in the presence of luminal 10-4 M enalaprilat. Thus the inhibition in proximal tubule transport by luminal enalaprilat was abrogated after acute renal denervation. In the next experiment we examined whether exogenous luminal angiotensin II would augment volume transport in the acutely denervated kidney. As seen in Fig. 4, proximal tubules from acutely denervated kidneys perfused with an ultrafiltrate-like solution containing 10-8 M angiotensin II had a rate of volume reabsorption of 2.67 ± 0.18 nl · mm-1 · min-1, significantly greater than those perfused with an ultrafiltrate-like solution alone (1.30 ± 0.21 nl · mm-1 · min-1, P < 0.01) and comparable to that seen in the control innervated kidney (2.97 ± 0.14 nl · mm-1 · min-1). These results are consistent with a decreased effect of intraluminal angiotensin II on proximal tubule volume transport after acute renal denervation.


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Fig. 4.   Proximal tubule Jv in acutely DNX rats with ultrafiltrate-like perfusate, ultrafiltrate-like perfusate plus 10-4 M enalaprilat, and ultrafiltrate-like perfusate with 10-8 M angiotensin II. Enalaprilat (10-4 M) did not reduce Jv in acute DNX rats. Addition of luminal 10-8 M angiotensin II increased Jv. n, No. of proximal tubules perfused. *P < 0.01 vs. acutely DNX and P < 0.05 vs. acutely DNX+10-4 M enalaprilat.


    DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The renin-angiotensin system and the sympathetic renal nerves play important roles in the regulation of fluid and solute reabsorption by the proximal tubule (2-5, 8, 11, 12, 14, 16, 17, 18, 24-26, 28). Recent studies have demonstrated that, in addition to the systemic renin-angiotensin system, an autonomous renin-angiotensin system exists within the proximal tubule that can "locally" synthesize and luminally secrete angiotensin II at levels 100-fold higher than plasma (2, 7, 12, 13, 16, 18, 20, 23-27, 29, 30). The effect of luminal angiotensin II on proximal tubule volume reabsorption has been controversial (2, 12, 16, 18, 24-26). A rabbit in vitro microperfusion study demonstrated that addition of 10-10 and 10-11 M angiotensin II to the luminal perfusate of the proximal tubule increased volume reabsorption by 142 and 204%, respectively (16). In contrast, a rat in vivo microperfusion study demonstrated a much smaller increase of only 20% in proximal tubule volume reabsorption after administration of luminal 10-11 and 10-12 M luminal angiotensin II, far less than the effect of systemic angiotensin II on proximal tubule transport (18). A split droplet study also demonstrated a small 20% increase in volume reabsorption with 10-9 M luminal angiotensin II but no effect with 10-11 M angiotensin II (12). Using in vivo microperfusion in the rat and in vitro microperfusion in the rabbit, our laboratory has found that addition of 10-6, 10-8, 10-10, and 10-11 M luminal angiotensin II had no effect on proximal tubule volume reabsorption (2, 24). The small or absent effect of luminal angiotensin II on proximal tubule volume reabsorption in the above studies is consistent with existing high levels of luminal angiotensin II measured in the range of 0.5-4 × 10-8 M (7, 23, 29).

The effect of luminal angiotensin II has also been examined by inhibiting its production or action in in vivo microperfusion studies. Addition of losartan, an AT1 angiotensin II-receptor antagonist, to the lumen of the proximal tubule reduced volume reabsorption by 35% (24). A comparable reduction in volume reabsorption (40%) was also noted with luminal administration of enalaprilat, an angiotensin-converting enzyme inhibitor (24). Subsequent addition of 10-8 M angiotensin II to the luminal perfusate containing 10-4 M enalaprilat resulted in an ~82% increase in proximal tubule volume reabsorption (24). Similar findings have been demonstrated in the rabbit proximal convoluted tubule perfused in vitro (2). Inhibition of proximal tubule transport by luminal enalaprilat in in vitro microperfusion is consistent with a direct tubular effect of luminal angiotensin II, independently of any confounding systemic factors. These results are consistent with a role for luminal angiotensin II to modulate proximal tubule transport independently of systemically circulating angiotensin II (2, 12, 16, 18, 24-26).

The proximal tubule is richly innervated by the sympathetic nervous system (1, 21). With the use of electron microscopy, renal nerve endings have been located adjacent to proximal tubule epithelial cells (1, 21). Acute renal denervation has been shown to decrease absolute proximal tubule water reabsorption in in vivo micropuncture studies (3, 4). These changes in transport occurred in the absence of changes in the glomerular filtration rate or renal blood flow and thus indicate a direct effect of the renal nerves on proximal tubule transport (3, 4). Our present in vivo microperfusion data demonstrate a large decrease in the proximal tubule volume reabsorptive rate after acute renal denervation, consistent with the above micropuncture studies.

Chronic renal denervation did not significantly decrease the proximal tubule volume reabsorptive rate. These results are at variance with the results of a previous micropuncture study, which demonstrated that chronic renal denervation reduced proximal tubule volume reabsorption (6). Our results were not due to inadequate renal denervation as there was a 90% decrease in renal norepinephrine content after mechanicochemical renal denervation. Furthermore, the rate of proximal tubule volume reabsorption was higher after chronic denervation than after acute denervation. This chronic adaptation in transport was not the result of an elevated compensatory role of intraluminal angiotensin II on proximal tubule transport. Inhibition of intraluminal angiotensin II production with luminal 10-4 M enalaprilat in acute and chronically denervated proximal tubules failed to alter transport, consistent with a small or absent effect for intraluminal angiotensin II on transport after renal denervation. Clearly, other adaptive responses contributed to the augmented proximal tubule transport in chronic denervation that were not addressed in this study (19).

An interaction between the systemic renin-angiotensin system and the sympathetic renal nerves has also been shown in prior studies, whereby the renal nerves require systemically circulating angiotensin II to augment renal sodium transport (11, 14). The mechanism by which circulating angiotensin II influences renal nerve activity is unclear but may involve facilitation of adrenergic transmission at the renal nerve-renal epithelial cell junction (11, 15). The renal nerves may also modulate the proximal tubule renin-angiotensin system. Renal denervation in Balb/c mice reduced the renal renin and renin mRNA content (33). Renal nerve stimulation in Wistar rats increased both renal renin mRNA and angiotensinogen mRNA abundance (22). The rise in renin and angiotensinogen mRNA by renal nerve stimulation were blocked by atenolol (22). Thus the renal nerves may facilitate the production of angiotensin II by augmenting the proximal tubule renin-angiotensin system. In addition to the renal nerves, other independent factors such as alterations in renal perfusion pressure and associated tubuloglomerular feedback interactions might also affect the intraluminal angiotensin II level and proximal tubule transport.

The effect of luminal angiotensin II on proximal tubule transport is also regulated by changes in the extracellular volume (26). The magnitude of the reduction in proximal tubule volume reabsorption observed with inhibition of luminal angiotensin II production using 10-4 M luminal enalaprilat was twofold greater during acute extracellular volume contraction than during acute extracellular volume expansion (26). Addition of 10-8 M angiotensin II to the lumen of the proximal tubule during volume expansion augmented the volume reabsorptive rate twofold to a rate comparable to that observed during volume contraction (26). These results are consistent with a role for luminal angiotensin II in modulating proximal tubule transport during altered states of extracellular volume (26). However, the mechanism by which changes in extracellular fluid volume modulate luminal angiotensin II and its effect on proximal tubule transport are unclear. It is interesting to speculate that the renal nerves may play a role in the modulation of the luminal angiotensin II-mediated component of proximal tubule transport during changes in extracellular volume. The potential role of the renal nerves to mediate changes in the effect of luminal angiotensin II on transport resulting from alterations in extracellular volume is consistent with the renal nerve's innervation of the proximal tubule and the regulation of its neural activity by changes in extracellular volume.

In summary, we find that acute and chronic renal denervation abolished the enalaprilat-sensitive component of proximal tubule volume transport. The addition of luminal 10-8 M angiotensin II augmented proximal tubule volume reabsorption in denervated tubules. These results are consistent with the renal nerves playing a role in the modulation of the intraluminally generated angiotensin II component of proximal tubule transport.


    ACKNOWLEDGEMENTS

We acknowledge the excellent secretarial assistance of Janell McQuinn and Laurel Johnson.


    FOOTNOTES

Address for reprint requests and other correspondence: A. Quan, Dept. of Pediatrics, Univ. of Texas Southwestern Medical Ctr., 5323 Harry Hines Blvd., Dallas, TX 75235 (E-mail: albert.aquan{at}.utsouthwestern.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 17 April 2000; accepted in final form 21 November 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Renal Fluid Electrolyte Physiol 280(3):F524-F529
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