Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system.

BACKGROUND: Bile acids (BAs) regulate cells by activating nuclear and membrane-bound receptors. G protein coupled bile acid receptor 1 (GpBAR1) is a membrane-bound G-protein-coupled receptor that can mediate the rapid, transcription-independent actions of BAs. Although BAs have well-known actions on motility and secretion, nothing is known about the localization and function of GpBAR1 in the gastrointestinal tract. METHODS: We generated an antibody to the C-terminus of human GpBAR1, and characterized the antibody by immunofluorescence and Western blotting of HEK293-GpBAR1-GFP cells. We localized GpBAR1 immunoreactivity (IR) and mRNA in the mouse intestine, and determined the mechanism by which BAs activate GpBAR1 to regulate intestinal motility. KEY RESULTS: The GpBAR1 antibody specifically detected GpBAR1-GFP at the plasma membrane of HEK293 cells, and interacted with proteins corresponding in mass to the GpBAR1-GFP fusion protein. GpBAR1-IR and mRNA were detected in enteric ganglia of the mouse stomach and small and large intestine, and in the muscularis externa and mucosa of the small intestine. Within the myenteric plexus of the intestine, GpBAR1-IR was localized to approximately 50% of all neurons and to >80% of inhibitory motor neurons and descending interneurons expressing nitric oxide synthase. Deoxycholic acid, a GpBAR1 agonist, caused a rapid and sustained inhibition of spontaneous phasic activity of isolated segments of ileum and colon by a neurogenic, cholinergic and nitrergic mechanism, and delayed gastrointestinal transit. CONCLUSIONS & INFERENCES: G protein coupled bile acid receptor 1 is unexpectedly expressed in enteric neurons. Bile acids activate GpBAR1 on inhibitory motor neurons to release nitric oxide and suppress motility, revealing a novel mechanism for the actions of BAs on intestinal motility.

degS (hhoB) is an essential Escherichia coli gene whose indispensable function is to provide sigma (E) activity.

DegS (HhoB), a putative serine protease related to DegP/HtrA, regulates the basal and induced activity of the essential Escherichia coli sigma factor sigma (E), which is involved in the cellular response to extracytoplasmic stress. DegS promotes the destabilization of the sigma (E)-specific anti-sigma factor RseA, thereby releasing sigma (E) to direct gene expression. We demonstrate that degS is an essential E. coli gene and show that the essential function of DegS is to provide the cell with sigma (E) activity. We also show that the putative active site of DegS is periplasmic and that DegS requires its N-terminal transmembrane domain for its sigma (E)-related function.

A method for isolation of rat renal microvessels and mRNA localization.

The objective of this study was to develop a technique to identify and dissect segments of the rat renal microcirculation and to apply reverse transcription (RT) to specific mRNAs with subsequent amplification of the cDNA by polymerase chain reaction (PCR) to evaluate gene expression. To circumvent the difficulty associated with visualizing specific microvessels, we intrarenally infused blue latex microparticles, 1-5 microns in diameter, with subsequent identification and microdissection of specific segments of the renal microvasculature under stereomicroscopy. To demonstrate its utility, we assessed expression of mRNAs encoding fibronectin and renin. As expected, mRNA encoding fibronectin was localized along the renal microcirculation, and mRNA encoding renin was primarily present in afferent arterioles and interlobular arteries. Identity of the amplified cDNA fragments was verified by sequencing. This perfusion-microdissection technique coupled to RT-PCR should be useful in the evaluation of gene expression along the renal microvasculature. It may also allow bridging of the gap between analysis of gene expression of rare mRNA species by in situ hybridization and physiology of the renal microcirculation.

Taxol inhibits progression of congenital polycystic kidney disease.

Polycystic kidney diseases (PKD) are the most common hereditary diseases of the human kidney and account for ten per cent of patients requiring renal transplantation or dialysis. Renal cyst formation has been attributed to enhanced cell proliferation, unbalanced cell death, abnormal targeting of membrane proteins, aberrant kidney development and tubular obstruction, but there is no treatment that blocks the formation and enlargement of renal cysts. We have now developed an in vitro model of spontaneous cyst formation that distinguishes polycystic kidney epithelium from its normal counterpart. Inhibitors of DNA, RNA and protein synthesis did not prevent in vitro cyst formation, but this was reversibly inhibited by ouabain, amiloride and the microtubule-specific agents colchicine, vinblastine and taxol. The cpk mouse is a well-characterized recessive PKD model and we find that cpk/cpk mice develop PKD and die from uraemia by 4-5 weeks of age, but when treated weekly with taxol they survive for more than 200 days with minimal loss of renal function, show limited collecting-dust cyst enlargement, and attain adult size. Our results indicate that the microtubule cytoskeleton has a central role in the pathogenesis of PKD in cpk mice and that taxol may also be useful in treating human PKD.

Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant nephron.

In the present micropuncture study, the autoregulation of glomerular capillary hydrostatic pressure (PG) in Munich-Wistar rats 24 h after 75% nephrectomy (Nx) or sham operation (Sh) was investigated. The effect of varying renal perfusion pressure (RPP) on paired determinations of directly measured PG was evaluated in glomeruli of nephrons in which distal fluid delivery was present (unblocked). Autoregulation of PG in Sh glomeruli with unblocked tubules occurred at RPP values between 99.5 +/- 1.0 and 132.1 +/- 1.0 mmHg. In contrast, in Nx glomeruli with unblocked tubules PG increased by 0.32 +/- 0.07 mmHg/mmHg increase in RPP over this same range of RPP (P less than 0.0001). To determine whether enhanced prostaglandins synthesis was responsible for the altered regulation of PG in Nx glomeruli, we repeated the micropuncture measurements in a setting of prostaglandin synthesis inhibition. Although prostaglandins synthesis inhibition did not affect the autoregulation of PG in Sh glomeruli, it did normalize the autoregulatory capacity for PG of Nx glomeruli with unblocked tubules. Thus, acute Nx is associated with a significant loss of the autoregulatory capacity for PG and this impairment appears to be related to a prostaglandin-mediated alteration of the responsiveness of the vascular effector site for autoregulation.

Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition.

These studies, using in vivo micropuncture techniques in the Munich-Wistar rat, document the magnitude of changes in glomerular and tubular function and structure 24 h after approximately 75% nephron loss (Nx) and compared these results with those obtained in sham-operated rats. The contribution of either nephron hypertrophy or renal prostaglandin to these adjustments in nephron function was also explored. After acute Nx, single nephron GFR (SNGFR) was increased, on average by approximately 30%, due primarily to glomerular hyperperfusion and hypertension. The approximately 45% reduction in preglomerular and the constancy in postglomerular vascular resistances was entirely responsible for these adaptations. Although increases in fluid reabsorption in proximal convoluted tubules correlated closely with increase in SNGFR, the fractional fluid reabsorption between late proximal and early distal tubular segments was depressed. Nephron hypertrophy could not be substantiated based on either measurements of protein content in renal tissue homogenates or morphometric analysis of proximal convoluted tubules. However, acute Nx was associated with increased urinary excretory rates per functional nephron for 6-keto-PGF1 alpha and TXB2. Prostaglandin synthesis inhibition did not affect function in control nephrons, but this maneuver was associated with normalization of glomerular and tubular function in remnant nephrons. The results suggest that enhanced synthesis of cyclooxygenase-dependent products is one of the earliest responses to Nx, and even before hypertrophy the pathophysiologic effects of prostaglandin may be important contributors to the adaptations in remnant nephron function.

Angiotensin II control of the renal microcirculation in rats with reduced renal mass.

It has been suggested that angiotensin II (ANG II) activation after renal ablation contributes to the altered glomerular dynamics and proteinuria that characterizes this model of chronic renal failure. In the present study, male Munich-Wistar rats underwent 75% renal ablation (Nx group). Two weeks later, micropuncture studies were performed in sham-operated rats (sham group) and Nx group rats during intravenous infusion of either a vehicle or two ANG II inhibitors, namely [Sar1, Ala8]ANG II or MK-421 administered at a rate of 0.3 and 1 mg.kg body wt-1.h-1, respectively. Acute ANG II inhibition in sham group had no effect on mean arterial pressure (MAP), glomerular dynamics, or proteinuria. In contrast, in Nx group ANG II inhibition lessened glomerular hypertension (from 64.7 +/- 1.0 to 55.4 +/- 1.7 mmHg, P less than 0.0001) the result of postglomerular vasodilation (P less than 0.01), normalized the glomerular ultrafiltration coefficient (from 0.038 +/- 0.002 to 0.005 +/- 0.002 nl.s-1.mmHg-1, P less than 0.0001), and attenuated proteinuria (from 42.1 +/- 6.5 to 28.1 +/- 5.4 micrograms/min, P less than 0.01). MAP, single-nephron GFR and plasma flow were unaffected. These results suggest that ANG II activity is enhanced in nephrectomy, contributing in a major way to altered glomerular dynamics and proteinuria.

Glomerular hemodynamic alterations during renal nerve stimulation in rats on high- and low-salt diets.

Renal adrenergic nerve activity exerts a major influence on glomerular hemodynamics and tubular fluid reabsorption. Modulation of the functional expression of adrenergic activity in the kidney can be mediated, in part, by the renin-angiotensin system and by prostanoid activity. Alterations in dietary salt intake have been previously shown to modify the activity of various vasoactive systems, including angiotensin and prostaglandin activity and thereby have a potential of modifying the glomerular hemodynamic response to a given renal adrenergic stimulus. Munich-Wistar rats were fed either a high-, low-, or normal salt diet for 2 wk before the day of the study. Measurements of glomerular hemodynamics were performed in both unstimulated with basal renal nerve traffic eliminated and during exogenous renal nerve stimulation (RNS) (3 Hz). RNS decreased glomerular capillary hydrostatic pressure and single-nephron plasma flow to a similar extent in all three dietary conditions via increases in afferent arteriolar resistance. The data demonstrated that dietary preconditioning does not alter the glomerular hemodynamic response to an exogenous, fixed RNS. Glomerular prostaglandin E2 production and plasma renin activity were significantly greater in rats fed a low-salt diet compared with either normal- or high-salt diet. The constancy of glomerular hemodynamic responses to RNS in spite of wide variations in dietary salt intake indicates that functional renal hemodynamic differences observed as a result of NaCl intake must be primarily the consequence of differences in renal nerve traffic and not hormonal alterations.

Effects of beta-adrenergic stimulation with isoproterenol on glomerular hemodynamics.

To evaluate the contribution of beta 1-2-adrenergic receptor stimulation to the regulation of single-nephron glomerular filtration rate (SNGFR), we examined by micropuncture techniques the effects of systemic and intrarenal infusion of isoproterenol on glomerular hemodynamics in plasma volume-expanded Munich-Wistar rats. Isoproterenol infused systemically was consistently associated with an elevation in glomerular capillary hydrostatic pressure difference (delta P) from 44.2 +/- 1.2 to 50.1 +/- 1.3 mmHg, P less than 0.01, the consequence of a 5.9-mmHg fall in Bowman's space hydrostatic pressure, P less than 0.005. The potentially beneficial effect of increased delta P on SNGFR was overcome by a 40% reduction in the glomerular ultrafiltration coefficient (LpA) from 0.043 +/- 0.003 to 0.026 +/- 0.003 nl.s-1.mmHg-1.g kidney wt-1, P less than 0.005, with a net effect of a modest 13% decline in SNGFR, P less than 0.01. In contrast, the intrarenal infusion of isoproterenol did not modify glomerular hemodynamics. Suppression of angiotensin II activity eliminated the influences of systemic isoproterenol infusion on LpA and delta P, the latter was the consequence of lower efferent arteriolar resistance. The findings suggest that systemic infusion of a beta 1-2-adrenergic agonist results in a decrease in LpA via angiotensin II effects and exerts a vasodilatory action on postglomerular vessels during angiotensin II inhibition.

Glomerular hemodynamic adaptations in remnant nephrons: effects of verapamil.

Chronic verapamil administration has been shown to reduce the renal dysfunction, glomerular sclerosis, and mortality in partially nephrectomized rats; the mechanism is unknown. Therefore, the present micropuncture study examines the effect of verapamil on glomerular hemodynamics of Munich-Wistar rats 4 wk after five-sixths nephrectomy. Whole-kidney function was similar in nephrectomized rats treated with verapamil (Nx-VER) and saline (Nx-SAL), and glomerular filtration rate (GFR) was one-third of control. Both Nx-VER and Nx-SAL rats exhibited a similar degree of glomerular hyperperfusion and hyperfiltration. However, mean glomerular capillary hydrostatic pressure difference (delta P) was lower in Nx-VER than Nx-SAL rats (42.4 +/- 1.2 vs. 47.2 +/- 1.0 mmHg, P less than 0.005) because of an increase in Bowman's space hydrostatic pressure (PBS) in Nx-VER rats (15.5 +/- 0.8 vs. Nx-SAL 11.9 +/- 0.7 mmHg, P less than 0.005). Glomerular ultrafiltration coefficient (LpA) was significantly lower in Nx-SAL (P less than 0.005) than in Nx-VER or control rats. Urinary protein excretion and the magnitude of glomerular sclerosis in Nx-SAL and Nx-VER rats were not different. In conclusion, chronic VER administration normalizes LpA and reduces delta P, by increasing PBS, in Nx rats, alterations that neutralize each other, leading to the constancy of single-nephron GFR.

Renal adrenergic effector mechanisms: glomerular sites for prostaglandin interaction.

Micropuncture experiments were performed in Munich-Wistar rats to ascertain the renal microcirculatory sites at which prostaglandins interact with the renal nerve and angiotensin II. Renal nerve stimulation (RNS) of 3 Hz alone decreased single-nephron glomerular filtration rate (SNGFR) by 30%, the consequence of 10 and 35% reductions in the glomerular capillary hydrostatic pressure difference (delta P) and the single-nephron plasma flow (SNPF), respectively. Pre- and postglomerular vascular resistances increased. RNS during prostaglandin inhibition (indomethacin) resulted in a 70% reduction in SNGFR, secondary to 1) a further diminution in delta P and in SNPF, via heightened pre- and postglomerular vasoconstriction and 2) a marked decline in the glomerular ultrafiltration coefficient (LpA), from 0.058 +/- 0.006 to 0.027 +/- 0.002 nl.s-1.mmHg-1.g kidney wt-1 (P less than 0.005). Acute angiotensin II inhibition (MK-421 and [Sar1,Ala8]angiotensin II) in rats pretreated with indomethacin partially attenuated the effects of RNS on vascular resistances and therefore on delta P, SNPF, and SNGFR and prevented the reduction in LpA. Thus vasodilatory prostaglandins act as local modulators of both renal nerve and angiotensin II constrictive actions on glomeruli and renal microcirculation.

Modulation of renal adrenergic effector mechanisms by calcium entry blockers.

Micropuncture studies in anesthetized Munich-Wistar rats were undertaken to investigate the effects of calcium channel blockade on the glomerular hemodynamic responses to 3-Hz renal nerve stimulation. Stimulation alone increased afferent and efferent arteriolar resistances by 85 and 35%, respectively. Because of these increases both single nephron plasma flow and glomerular capillary hydrostatic pressure difference fell to levels significantly below control, leading to a 26% reduction in single nephron filtration rate (P less than 0.005). These changes, however, were largely attenuated during calcium channel blockade (verapamil, nifedipine). Single nephron filtration rate was only decreased by 14% (P less than 0.05) due to a reduction in single nephron plasma flow. The role of angiotensin II on the residual vasoconstrictive effect of stimulation was also investigated. Pretreatment with an angiotensin-converting enzyme inhibitor (MK 421) of rats infused with verapamil abolished the residual vasoconstriction. The data suggest that calcium influx is an important step for the vasoconstrictive effects of the renal nerves. Additionally, angiotensin II contributes to increased vascular resistance during renal nerve stimulation via a separate, calcium channel mechanism.

Changes in glomerular hemodynamic response to angiotensin II after subacute renal denervation in rats.

We examined the changes in glomerular hemodynamics produced by angiotensin II (AII) in both normal Munich-Wistar rats and rats which were unilaterally renal denervated (measured kidney) 4-6 d prior to the measurement periods. Measurements of glomerular dynamics were performed in a control period after plasma volume expansion and during infusion of 11 ng X 100 g body wt-1 X min-1 of AII. The glomerular hydrostatic pressure gradient increased from 38 +/- 1 to 49 +/- 1 mmHg in denervated rats compared with a lesser response in controls (from 39 +/- 1 to 45 +/- 1 mmHg, P less than 0.05). Single nephron plasma flow decreased from 213 +/- 17 to 87 +/- 4 nl X min-1 X g kidney wt (KW)-1 in denervated kidneys versus a more modest decrease in control kidneys (from 161 +/- 9 to 102 +/- 5 nl X min X gKW-1). These changes were due to a greater increase in both afferent and efferent arteriolar resistance after AII infusion in denervated compared with control kidneys. Glomerular AII receptor maximum binding was 1,196 +/- 267 fmol/mg protein in denervated kidneys compared with 612 +/- 89 fmol/mg protein (P less than 0.01) in controls with no change in receptor affinity. We conclude the subacute unilateral renal denervation results in renal vasodilation, denervation magnifies the vasoconstrictive effect of AII infusion on glomerular hemodynamics, and the observed increased response to AII after denervation is associated with increases in glomerular AII receptors.

Effects of the anaphylatoxin, C5a, on renal and glomerular hemodynamics in the rat.

The effects of intrarenal infusion of the complement-derived anaphylatoxin, C5a, upon glomerular hemodynamics were examined in the Munich-Wistar rat, a strain with glomeruli on the kidney surface. Human C5a (1.5 micrograms/min) or vehicle was infused into the left renal artery for 12 min, and glomerular capillary (PG) and Bowman's space pressures, nephron plasma flow (SNPF) afferent and efferent arteriolar protein concentrations, nephron filtration rate (SNGFR) and the glomerular ultrafiltration coefficient (LpA) determined. Human C5a infusion resulted in a reduction in SNPF due to increased efferent arteriolar resistance, and PG increased which maintained SNGFR constant. LpA was numerically lower but not significantly decreased. Infusion of porcine C5ades Arg decreased glomerular filtration rate and renal blood flow. No polymorphonuclear leukocytes were observed within glomerular capillaries of C5a infused rats, and rat leukocytes did not exhibit receptors for human C5a infused. Renal artery infusion of either human C5a or porcine C5a resulted in renal hemodynamic alterations and, as documented for human C5a, effects of C5a upon renal vascular resistance can be added to the known effect of C5a on the polymorphonuclear leukocyte.

Functional basis for the glomerular alterations in uranyl nitrate acute renal failure.

We have examined the acute renal failure that occurs after uranyl nitrate administration in the rat and the specific effects of pretreatment of rats with angiotensin converting enzyme inhibitor (CEI), plasma volume expansion (PVE) after uranyl nitrate, and a combination of these treatments. We utilized a combination of micropuncture measurements of glomerular hemodynamics, cage studies, and histologic examination of renal tissue to evaluate the degree of acute renal failure in all groups studied. Uranyl nitrate (UN) (25 mg/kg body wt) administration caused a reduction in the nephron filtration rate (SNGFR) (39.4 +/- 1.6 to 24.8 +/- 2.9 nl X min-1 X g kidney wt-1, P less than 0.02) as a result of a major decrease in the glomerular ultrafiltration coefficient (LpA) from control values (greater than or equal to 0.085 +/- 0.008 to 0.035 +/- 0.007 nl X sec-1 X mm Hg-1 X g kidney wt-1, P less than 0.01). Treatments with CEI, PVE, and the combination of CEI and PVE in rats receiving UN restored 0.38 +/- LpA to normal values (greater than 0.061 +/- 0.009, 0.091 +/- 0.020, and 0.138 +/- 0.020 nl X sec-1 X mm Hg-1 X g kidney wt-1, respectively). Cage studies revealed that CEI treatment prevented oliguria and resulted in major volume losses and reduction in weight. However, rats died after a similar period after UN, but probably by different mechanisms. Analysis of renal ultrastructure revealed equivalent tubular damage in all experimental groups. Alterations in LpA after UN are functional in nature and are potentially preventable and reversible by a combination of treatments with CEI and PVE.

Angiotensin II in adrenergic-induced alterations in glomerular hemodynamics.

UNLABELLED: Micropuncture analysis of glomerular ultrafiltration (SNGFR) was conducted in Munich-Wistar rats to assess the functional responses to moderate-frequency (3-Hz) renal nerve stimulation. Angiotensin II inhibition (ANG II-inhib) was produced by the intravenous administration of [Sar1, Ala8] angiotensin II or MK 421 to investigate whether it modulates the effects of renal nerve stimulation. Micropuncture measurements were obtained before and during renal nerve stimulation. Renal nerve stimulation decreased SNGFR approximately 25% (from 49.9 +/- 2.3 to 38.0 +/- 1.4 nl X min-1 X g kidney wt-1), the result of decreased glomerular capillary hydrostatic pressure gradient and nephron plasma flow. These decreases were due to increased afferent (approximately 43%) and efferent (approximately 30%) arteriolar resistances, since the glomerular ultrafiltration coefficient remained unaffected. The effects of renal nerve stimulation during ANG II-inhib were less in magnitude than in renal nerve stimulation alone: SNGFR decreased from 48.0 +/- 1.5 to 44.8 +/- 2.0 nl X min-1 X g kidney wt-1 after renal nerve stimulation. The net renal production of norepinephrine was augmented by renal nerve stimulation but it was not influenced by ANG II-inhib. IN CONCLUSION: renal nerve stimulation can regulate glomerular ultrafiltration by altering vascular resistances, and angiotensin II appears to be a critical factor for the full functional expression of renal nerve stimulation at the glomerulus.

Age-dependent renal effects of intrarenal dopamine infusion.

Three groups of anesthetized puppies 16.4 +/- 1.2 (group I), 29.6 +/- 1.6 (group II), and 49.8 +/- 2.5 (group III) days of age were used to assess the renal response to graded doses of dopamine infusion into the renal artery. Dopamine infusion at 1 microgram X kg-1 X min-1 increased renal blood flow (RBF) from 3.61 +/- 0.31 to 4.22 +/- 0.43 ml X min-1 X g kidney wet wt-1 (P less than 0.05) only in the older puppies (group III). Glomerular filtration rate (GFR) increased in groups II and III from control values of 0.69 +/- 0.14 and 0.61 +/- 0.08 to 1.08 +/- 0.19 and 0.83 +/- 0.05 ml X min-1 X g kidney wet wt-1, respectively (P less than 0.05). However, urinary flow rate and sodium excretion were variably affected. Because dopamine is known to stimulate both alpha- and beta-adrenoceptors in addition to dopamine receptors, two additional groups of puppies 11.2 +/- 1.2 (group IV) and 72.8 +/- 2.4 (group V) days of age were studied to evaluate the renal effects of dopamine during the continuous intrarenal infusion of phentolamine and nadolol (an alpha- and a beta-adrenergic blocker, respectively). Dopamine elicited increases in RBF only in the older puppies (P less than 0.05). GFR, urinary flow rate, and sodium excretion increased in both groups; however, the magnitude of the change was greater for each parameter in the older group (P less than 0.05). These experiments suggest a maturational process for specific dopamine receptors and/or effector response, which may affect the observed age-dependent increases in RBF, GFR, and renal sodium handling.

A functional role for the tubuloglomerular feedback mechanism.

Ever increasing evidence exists that the tubuloglomerular feedback system exerts a major influence on overall renal function. Several examples are potentially pertinent to clinical medicine in which there is reasonable evidence that activation or suppression of tubuloglomerular feedback mechanisms contribute significantly to alterations in normal renal physiology. However, in most examples reported, the feedback mechanism is one of several influences acting in concert to determine the final nephron filtration rate, its respective determinants, and the relationship of filtration to the rate of tubular reabsorption. A more complete understanding of all the factors which influence and modify the functional role of tubuloglomerular feedback mechanisms will aid our understanding significantly and the consequent therapy of a variety of altered physiologic conditions.

Analysis of renal denervation in the hydropenic rat: interactions with angiotensin II.

Nephron filtration rate (SNGFR), its determinants, and proximal tubular reabsorption were measured in hydropenic Munich-Wistar rats with sham-operated (sham) or denervated (DNx) kidneys before and during the administration of [Sar1, Ala8]angiotensin II or SQ 14225. The glomerular ultrafiltration coefficient (LpA) was significantly lower in DNx than in sham rats (P less than 0.025). However, SNGFR was not altered due to an offsetting increment in transcapillary glomerular hydrostatic pressure (delta P) in DNx (P less than 0.005). The marked increment of delta P in DNx was due to an increase in the glomerular capillary hydrostatic pressure, secondary to decreased afferent arteriolar resistance. The infusion of angiotensin II inhibitors to denervated kidneys completely normalized LpA but did not alter sham values. SQ 14225 but not [Sar1, Ala8]angiotensin II infusion provided a nephron plasma flow-dependent increase in SNGFR, secondary to a striking reduction in both glomerular vascular resistances. Endogenous angiotensin II activity may be enhanced by renal denervation, and angiotensin II acts to reduce LpA in this condition and may modulate the final level of renal vascular resistances after acute renal denervation.