Renal and systemic nitric oxide synthesis in rats with renal mass reduction (original) (raw)
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Journal of the American Society of Nephrology, 2003
Wistar Furth (WF) rats do not develop renal injury after severe reduction of renal mass. Because clinical and animal studies suggested that nitric oxide (NO) deficiency occurs and may contribute to chronic renal disease (CRD), the status of the NO system in WF versus Sprague Dawley (SD) rats was examined with the 5/6 renal ablation/infarction (A/I) model of CRD. Eleven weeks after A/I, SD rats developed proteinuria, severe kidney damage, decreased renal function, and marked decreases in total and renal NO synthase (NOS), specifically neuronal NOS. In contrast, WF rats exhibited elevated baseline and maintained post-A/I total NO production, with no decrease in renal cortex NOS activity despite a decrease in remnant neuronal NOS abundance. When low-dose chronic Nω-nitro-L-arginine methyl ester treatment was added for WF A/I-treated rats, rapid progression of CRD was observed. In conclusion, elevated NO production in WF rats was associated with protection from the progression of CRD after renal mass reduction. The protection might be attributable to greater total and renal NO-generating capacity and increased nephron number, compared with SD rats. NOS inhibition rendered WF rats susceptible to progression, suggesting a possible critical threshold for NO production, below which renal injury occurs.
Kidney International, 1993
Enhanced nitric oxide synthesis in uremia: Implications for platelet dysfunction and dialysis hypotension. Nitric oxide (NO), a potent vasodilator which also inhibits platelet adhesion and aggregation, is generated by endothelial cells and platelets from its precursor L-arginine. Since N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, normalizes the prolonged bleeding time of uremic rats, it has been suggested that bleeding associated with uremia was due to an excessive NO formation. With the present study we sought to evaluate whether in patients with chronic renal failure-like in uremic ratsdefective platelet aggregation were associated with excessive formation of NO and whether uremic plasma promotes NO synthesis by cultured vascular endothelium. Data indicated that plasma L-arginine was higher in uremics than in controls, uremic platelets generated more NO than control platelets, and intraplatelet levels of cGMP (the NO second messenger) were also higher in uremic than in control platelets.
Nitric Oxide Modulates Vascular Disease in the Remnant Kidney Model
The American Journal of Pathology, 2002
Soc Nephrol, 12:1434, 2001). Given that nitric oxide (NO) is a potent endothelial cell survival factor, we hypothesized that stimulating (with L-arginine) or blocking (with nitro-L-arginine methyl ester, (L-NAME)) NO synthesis could modulate the integrity of the microvasculature and hence affect progression of renal disease. Rats underwent 5/6 nephrectomy (RK) and then were randomized at 4 weeks to receive vehicle, L-NAME , or L-arginine for 4 weeks. Systolic blood pressure and renal function was measured, and tissues were collected at 8 weeks for histological and molecular analyses. The effect of modulation of NO on vascular endothelial growth factor (VEGF) expression in rat aortic vascular smooth muscle cells (SMC) and mouse medullary thick ascending limb tubular epithelial cells (mTAL) was also studied. Inhibition of NO with L-NAME was associated with more rapid progression compared to RK alone, with worse blood pressure, proteinuria, renal function, glomerulosclerosis, and tubulointerstitial fibrosis. The injury was also associated with more glomerular and peritubular capillary endothelial cell loss in association with an impaired endothelial proliferative response. Interestingly, the preglomerular endothelium remained intact or was occasionally hyperplastic, and this was associated with a pronounced proliferation of the vascular SMCs with de novo expression of VEGF. Cell culture studies confirmed a divergent effect of NO inhibition on VEGF expression, with inhibition of VEGF synthesis in mTAL cells and stimulation of VEGF in vascular SMC. In contrast to the effects of NO inhibition, stimulation of NO with L-arginine had minimal effects in this rat model of progressive renal disease. These studies confirm that blockade of NO synthesis accelerates progression of renal disease in the remnant kidney model, and support the hypothesis that one of the pathogenic mechanisms may involve accelerated capillary loss and impaired angiogenesis of the renal microvasculature. Interestingly, inhibition of NO synthesis did not lead to a loss of the preglomerular endothelium, which may relate to the effect of NO blockade to stimulate VEGF synthesis in the adjacent vascular smooth muscle cell.
Nitric oxide in the kidney: Physiological roles and regulation
Physiological roles of nitric oxide (NO) in the kidney include the regulation of renal and glomerular haemodynamics, mediation of pressure natriuresis, maintenance of medullary perfusion, blunting of tubuloglomerular feedback (TGF), inhibition of tubular sodium reabsorption and modulation of renal sympathetic nerve activity. The net effect of NO in the kidney is to promote natriuresis and diuresis and NO plays an important role in the renal adaptation to variations of dietary salt intake. Reduction of NO production in the renal medulla, either pharmacologically or genetically, has a great impact on the delivery of blood to the medulla and on the long-term regulation of sodium excretion and blood pressure. Conversely, infusion of L-arginine to increase nitric oxide, abrogates hypertension and enhances medullary blood flow. It is evident that medullary NO production serves as an important counterregulatory factor to buffer vasoconstrictor hormone-induced reduction of medullary blood f...
The influence of nitric oxide synthase 1 on blood flow and interstitial nitric oxide in the kidney
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001
The role of nitric oxide (NO) produced by NO synthase 1 (NOS1) in the renal vasculature remains undetermined. In the present study, we investigated the influence of systemic inhibition of NOS1 by intravenous administration of Nω-propyl-l-arginine (l-NPA; 1 mg · kg−1· h−1) and N5-(1-imino-3-butenyl)-l-ornithine (v-NIO; 1 mg · kg−1· h−1), highly selective NOS1 inhibitors, on renal cortical and medullary blood flow and interstitial NO concentration in Sprague-Dawley rats. Arterial blood pressure was significantly decreased by administration of both NOS1-selective inhibitors (−11 ± 1 mmHg with l-NPA and −7 ± 1 mmHg with v-NIO; n = 9/group). Laser-Doppler flowmetry experiments demonstrated that blood flow in the renal cortex and medulla was not significantly altered following administration of either NOS1-selective inhibitor. In contrast, the renal interstitial level of NO assessed by an in vivo microdialysis oxyhemoglobin-trapping technique was significantly decreased in both the renal ...
Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney
Journal of the American Society of Nephrology, 2002
ABSTRACT. The functional role of the NO synthase (NOS) isoforms in the normal or diseased kidney is uncertain. This study examined the renal expression of the endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms by both immunohistochemistry and Western blot analyses in sham-operated rats (S) and in rats subjected to 5/6 nephrectomy (Nx). Primary antibodies from two different sources were used to detect iNOS. Additional S and Nx rats were chronically treated with aminoguanidine (AG), a selective iNOS inhibitor. All three isoforms were clearly expressed in S kidney. Their renal abundance, evaluated by Western blot analysis, fell in Nx rats. With the use of anti-iNOS antibodies from two distinct sources, the immunohistochemical analysis showed the presence of what appeared to be two distinct iNOS fractions: a “tubular” fraction, present in S and with decreased intensity in Nx; and an “interstitial” fraction, observed only in inflamed areas of Nx rats. AG treatment greatly...
Circulation Research, 1998
Inhibition of NO synthesis has recently been shown to increase oxygen extraction in vivo, and NO has been proposed to play a significant role in the regulation of oxygen consumption by both skeletal and cardiac muscle in vivo and in vitro. It was our aim to determine whether NO also has such a role in the kidney, a tissue with a relatively low basal oxygen extraction. In chronically instrumented conscious dogs, administration of an inhibitor of NO synthase, nitro-L-arginine (NLA, 30 mg/kg IV), caused a maintained increase in mean arterial pressure and renal vascular resistance and a decrease in heart rate (all PϽ0.05). At 60 minutes, urine flow rate and glomerular flow rate decreased by 44Ϯ12% and 45Ϯ7%, respectively; moreover, the amount of sodium reabsorbed fell from 16Ϯ1.7 to 8.5Ϯ1.1 mmol/min (all PϽ0.05). At this time, oxygen uptake and extraction increased markedly by 115Ϯ37% and 102Ϯ34%, respectively (PϽ0.05). Oxygen consumption also significantly increased from 4.5Ϯ0.6 to 7.1Ϯ0.9 mL O 2 /min. Most important, the ratio of oxygen consumption to sodium reabsorbed increased dramatically from 0.33Ϯ0.07 to 0.75Ϯ0.11 mL O 2 /mmol Na ϩ (PϽ0.05), suggesting a reduction in renal efficiency for transporting sodium. In vitro, both a NO-donating agent and the NO synthase-stimulating agonist bradykinin significantly decreased both cortical and medullary renal oxygen consumption. In conclusion, NO plays a role in maintaining a balance between oxygen consumption and sodium reabsorption, the major ATP-consuming process in the kidney, in conscious dogs, and NO can inhibit mitochondrial oxygen consumption in canine renal slices in vitro.
Evidence for the Presence of an Unusual Nitric Oxide- and Citrulline-Producing Enzyme in Rat Kidney
Biochemical and Biophysical Research Communications, 1997
NO is formed from the terminal guanidino nitrogen We have found an enzymatic activity obtained from of L-arginine by NO synthase (NOS) (10). The isoforms rat kidney capable of producing citrulline and NOx of this enzyme exist in constitutive forms in vascular (nitrate and nitrite) which was resistant to inhibition endothelium (eNOS) (11) and cerebellum, (nNOS) (12) by conventional arginine analogues. This enzyme acand these isoforms are calcium and calmodulin-depentivity does not require any calcium or calmodulin and dent. The inducible isoform (iNOS) which is calcium was found to be induced during pregnancy. This and calmodulin-independent is found in macrophages unique enzyme was found to be tissue and species spe-(13), in endothelial cells (14), vascular smooth muscle cific. Another unique feature of this enzyme is that cells (15) and hepatocytes (16). This isoform is induced it did not bind to 2 5-ADP-sepharose under standard after several hours of exposure to cytokines and endoconditions. Western blot analysis of the 100,000 g kidtoxins. These three distinct isoforms have all been reney supernatant using monoclonal antibody for macported to be present in the mammalian kidney (17rophage inducible nitric oxide synthase failed to pro-19). eNOS is expressed in vascular endothelium and duce a band for inducible nitric oxide synthase. HPLC tubular epithelium (17), nNOS is found in the macula and capillary ion analysis for nitrate and nitrite (NOx) densa cells and the epithelium of Bowman's capsule showed clear peaks for [ 3 H] L-citrulline and NOx, respectively, which were not changed either in the ab-(18), whereas iNOS is present in the proximal tubule, sence of calcium and calmodulin or in the presence of glomerulus, and in the inner medullary collecting duct 300 mM S-ethylisothiourea, which has been shown to (19). Despite the growing evidence suggesting an imbe a very potent and selective inhibitor of inducible portant role for NO in renal function, the expression of nitric oxide synthase with a Ki of about 14.7 nM. These iNOS in the kidney is not very clear. Recently, Tojo et results suggest the possible existence of another isoal. (20) reported that a polyclonal iNOS antibody from form of nitric oxide synthase with very distinct propvascular smooth muscle cells did not immunolabel gloerties from the known isoforms.
American Journal of Nephrology, 2010
Background/Aims: The C57Bl6 mouse is resistant to chronic kidney disease (CKD) induced by reduction of renal mass (RRM). Nitric oxide (NO) deficiency exacerbates CKD progression so this study investigated whether combination of RRM and NO deficiency would render the C57Bl6 mouse vulnerable to CKD. Methods: We used wild-type (WT) mice with RRM, chronic NO synthase (NOS) inhibition and a combination. Also, endothelial NOS (eNOS) knockout (KO) C57Bl6 mice were studied with and without RRM. Primary endpoints were albuminuria and structural damage. Results: Both nonselective (+ L-NAME) and neuronal NOS 'selective' (+7NI) NOS inhibition greatly exacerbated the albuminuria and structural damage seen with RRM in the WT mice; NOS inhibition alone had little effect. The eNOS KO mice showed marked structural damage and significant albuminuria in the shams and RRM produced minimal exacerbation of structural damage although the albuminuria was massively amplified. Conclusion: These studies demonstrate that the C57Bl6 mouse is rendered vulnerable to RRM-induced CKD when concom