Abstract. Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P Ͻ 0.01), and inhibition of NO synthesis with N-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P Ͻ 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.Nitric oxide (NO) is a vasodilator that contributes to the regulation of regional blood flow and BP by tonically lowering vascular resistance (1,2). This effect is mediated through activation of soluble guanylate cyclase, which increases cellular cyclic guanosine monophosphate (cGMP), resulting in vascular relaxation and decreased vascular resistance (3). In the kidney, continuous release of NO derived from the vascular endothelium is an important determinant of basal perfusion and resistance. Release of NO can be stimulated by changes in the hydromechanical forces associated with pulsatile blood flow (4 -6). Vascular shear stress is a primary stimulus for endogenous NO production from the endothelium (7-10). Miller et al. (7,8) demonstrated in vitro that chronic alterations in local blood flow, produced by opening an arteriovenous anastomosis, increased endothelium-dependent relaxation. Increasing coronary blood flow by chronic cardiac pacing or exercise also enhanced endothelium-dependent dilatation (9,10). Although the mechanism responsible for flow-induced dilatation is not completely understood, there is considerable evidence that it is mediated, in part, by [11][12][13][14][15]. Removing the endothelium or inhibiting NO synthesis blocks flow-induced dilation (13,15). Studies in dogs have demonstrated that chronic exercise enhances the release of nitrites from the coronary arteries and microvessels, accompanied by increased blood flow, and this is associated with increased expression of the endothelial i...

Abstract-We compared the phenotype of two common mouse models, C-57BL/6J (C57), which carries only the Ren-1 c gene, and 129/SvJ (Sv-129), with both Ren 1 d and Ren-2. We hypothesized two renin gene Sv-129 would have increased blood pressure and the renin-angiotensin system would be more influential in regulating renal function compared with one renin gene mice. Sv-129 consistently had higher blood pressure than C-57, whether conscious (128 versus 108 mm Hg, PϽ0.001) or anesthetized (102 versus 88 mm Hg, PϽ0.001). Plasma renin concentration in both conscious and anesthetized C-57 mice was 3-to 4-fold higher than in Sv-129 (PϽ0.05), whereas renal cortical renin content was 2.5-fold higher (PϽ0.005). Renal blood flow and renal vascular resistance were the same in C-57 and Sv-129. Exogenous angiotensinogen produced identical pressor and renal vasoconstrictor responses in both strains. Blocking AT 1 receptors with losartan reduced blood pressure by 19 mm Hg in both strains. Nitric oxide synthase inhibition by L-NAME increased blood pressure by 29 mm Hg in C-57 and 35 mm Hg in Sv-129 mice, but the decrease in renal blood flow was 30% less in C-57 (PϽ0.025). We conclude that Sv-129 mice with two renin genes have higher blood pressure but lower plasma and renal renin than C-57 mice with one renin gene. Renin substrate may limit angiotensin II production in the mouse. In Sv-129, the influence of nitric oxide on renal but not systemic resistance may be exaggerated. Renin from Ren-2 may act independently of normal renin control mechanisms. Key Words: angiotensin Ⅲ angiotensinogen Ⅲ endothelium Ⅲ mouse Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ renin T he potent vasoconstrictor hormone angiotensin II (AngII) is the active product of the renin-angiotensin system. AngII is typically produced through the rate-limiting cleavage of the substrate angiotensinogen by the enzyme renin.

The severity of polycystic kidney diseases (PKD) depends on the counterbalancing of genetic predisposition and environmental factors exerting permissive or protective influence on cyst development. One poorly characterized phenomenon in the cystic epithelium is abnormal purinergic signaling. Earlier experimental studies revealed the high importance of the ionotropic P2X receptors (particularly, P2X7) in the pathophysiology of the cyst wall. To study mechanisms of P2X7 involvement in cyst growth and aspects of targeting these receptors in PKD treatment we performed a CRISPR/SpCas9-mediated global knockout of the P2rx7 gene in PCK rats, a model of autosomal recessive PKD (ARPKD). A single base insertion in exon 2 of the P2rx7 gene in the renal tissues of homozygous mutant animals leads to lack of P2X7 protein that did not affect their viability or renal excretory function. However, PCK. P2rx7 rats demonstrated slower cyst growth (but not formation of new cysts) compared with heterozygous and PCK. P2rx7+ littermates. P2X7 receptors are known to activate pannexin-1, a plasma channel capable of releasing ATP, and we found here that pannexin-1 expression in the cystic epithelium is significantly higher than in nondilated tubules. P2X7 deficiency reduces renal pannexin-1 protein expression and daily urinary ATP excretion. Patch-clamp analysis revealed that lack of P2X7 increases epithelial sodium channel activity in renal tissues and restores impaired channel activity in cysts. Interpretation of our current data in the context of earlier studies strongly suggests that P2X7 contributes to cyst growth by increasing pannexin-1-dependent pathogenic ATP release into the lumen and reduction of sodium reabsorption across the cyst walls.

It is well established that two-kidney, one clip renovascular hypertension can be rapidly reversed by unclipping. We hypothesized that rapid renal reperfusion and the subsequent fall in blood pressure are mediated in part by nitric oxide, the endothelium-derived relaxing factor. We tested whether the hypotensive response to unclipping could be blocked by nitric oxide synthesis inhibition using a bolus of 10 mg/kg body wt N omega-nitro-L-arginine methyl ester. Rats were made hypertensive by placing a silver clip on the left renal artery. After 4 weeks, they were anesthetized and either not treated (controls) or had nitric oxide synthesis blockade. After 10 minutes, the clip was removed and blood pressure monitored over 60 minutes. Initial pressure in controls was 157 +/- 8 mm Hg, and heart rate was 310 +/- 21 beats per minute. Unclipping resulted in pressure falling to 125 +/- 6 mm Hg within 45 minutes (P < .005). Heart rate was unchanged (312 +/- 9 beats per minute). In contrast, nitric oxide synthesis inhibition increased blood pressure from 149 +/- 6 to 174 +/- 9 mm Hg (P < .001). Unclipping did not change blood pressure, which was 167 +/- 8 mm Hg after 60 minutes (P < .005 versus controls), and heart rate remained unchanged (282 +/- 13 versus 276 +/- 16 beats per minute). We determined the blood flow to the clipped kidneys using radioactive microspheres. Unclipping untreated hypertensive rats resulted in a 10-fold increase in renal blood flow (P < .001), concomitant with a decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)