Nitric oxide in the kidney

IN FOCUSNitric oxide in the kidneyPontus B. PerssonPontus B. Persson Johannes-Müller Institut für Physiologie, 10117 Berlin, GermanyPublished Online:01 Nov 2002https://doi.org/10.1152/ajpregu.00445.2002MoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations bastron and kaloyanides(2) had already investigated the effects of sodium nitroprusside in the isolated kidney 8 years before the postulate of an endothelium-derived relaxing factor was made by Furchgott and Zawadzki (14). More recent studies aim at the importance of nitric oxide (NO) for kidney development (36, 37) and kidney function during pregnancy, efferent and afferent renal nerve activity (21), renal hemodynamics (17) and excretion (26, 39), as well as renal injury and pathophysiology (6, 25).Renal vascular resistance is low in pregnancy, possibly relying on NO (7, 20, 33), which could be released by relaxin (9). Hefler et al. (16) found that mice either deficient for endothelial NO synthase (eNOS) or overexpressing angiotensinogen and mice with mutations in both genes showed higher blood pressures throughout pregnancy compared with common laboratory strains (16). This increased blood pressure was not of renal origin; at least the measured renal functional parameters did not significantly change. At first sight, this might seem surprising: a reduced renal arterial smooth muscle cell contractility has been observed in pregnant rats. In these pregnant rats, unspecific inhibition of NO synthesis enhances renal vascular cell contraction contractility, presumably by increases of intracellular Ca2+ concentration (30). NOS inhibition increases vascular resistance in many beds in the pregnant rabbit (3). It also abrogates the reduced myogenic reactivity of small renal vessels from gravid rats (15). The latter occurs without affecting myogenic reactivity in arteries from virgin animals (15). However, it seems that neuronal NOS (nNOS), and not eNOS, is the NOS isoform that helps maintain renal perfusion and filtration during pregnancy (1). Although nNOS inhibition does not alter basal renal blood flow in normal rats (19), this may be different in pregnancy, which would explain the insignificant changes of creatinine clearance in pregnant eNOS-deficient mice (16).There can be little doubt that renal sympathetic efferent nerves are important for renal function (10, 11, 24, 27, 29). Conversely, many features of the kidney's afferent innervation are still being unraveled (21, 22). nNOS in the kidney is not only localized in the macula densa cells; the renal pelvis also seems to contain nNOS. It is colocalized with substance P and CGRP in renal pelvic sensory nerves (21). Release of substance P produced by increased renal pelvic pressure appears to enhance NO production, which, in turn, results in desensitization of substance P receptors via increased cGMP production. Activation of NO may function as an inhibitory neurotransmitter, regulating the activation of renal mechanosensory nerve fibers by mechanisms related to activation of substance P receptors (21). In theory, this mechanism is a second potential link between nNOS and renal functional changes that can be important during pregnancy or pathophysiological states.The renal medullary circulation is important for blood pressure (12, 13) and fluid and electrolyte homeostasis (8). Reduction of medullary blood flow, e.g., by local infusion of nNOS antisense, can lead to salt-induced hypertension (28). However, salt-dependent hypertension is also found during inducible NOS (iNOS) inhibition. Moreover, the effect of blocking nNOS on blood pressure without any further challenge has been a matter of dispute (19, 31). Changes in local renal blood flow do not seem to occur when nNOS is blocked (19). An important role of medullary NO production might be associated with the activation of α2-adrenergic receptors: this NO release counteracts the vasoconstrictor effects of norepinephrine in the renal medulla, which is essential for the maintenance of renal medullary blood flow (42).As of yet, the relevance of NO for many kidney functions is not clear. For instance, NO has been reported to stimulate, inhibit, and to not change renin levels (23, 32). This might rely on the potential of NO to inhibit phosphodiesterase 3 (5, 35), which, in turn, degrades cAMP. Moreover, NO blockade increases blood pressure (4, 18, 41), which reduces renin release (34, 38) by a different mode of action than does NO.NO is also essential in regulating proximal tubular reabsorption of fluid, sodium, bicarbonate, and phosphate. NO controls most renal transporters and the permeability of the proximal tubule. Whether the renal tubules, particularly the proximal tubule, produce NO under basal conditions is still unclear. However, it seems that the proximal tubule is exposed to NO and that great amounts of NO are released by a variety of stimuli (25). This may also be of pathophysiological importance: enhanced production of NO, perhaps iNOS from macrophages, may participate in hypoxic/ischemic proximal tubular injury (25). Glomerular NO production is also increased by ischemia (40). In this context, NO seems to stem from the eNOS isoform and has a protective influence. Unspecific blockade of the NOS isoforms enhance the severity of renal ischemia. A protective effect of NO in certain forms of renal failure is supported by experiments using vena cava occlusion (6). This procedure leads to acute renal failure by impairing renal venous draining. The renal outer medulla is pivotal in the pathophysiology of ischemic renal failure. The long-term outcome relies more on this region of circulation than on glomerular filtration. Remarkably, renal failure by vena cava occlusion is aggravated by NO depletion (6).N-acetyl-l-cysteine, a free radical scavenger, enhanced outer medullary blood flow in this model of renal failure and ameliorated the renal failure. The effect of the free radical scavenger, however, relied on an intact NO production (6).Taken together, NO plays an important role for maintaining volume, electrolyte, and blood pressure homeostasis. This is brought about by controlling the local renal circulation, modulating renal efferent and afferent nerve activity, and by directly affecting the reabsorption of fluids and electrolytes. Changes occurring during pregnancy and in various pathophysiological states, such as acute renal failure or salt-sensitive hypertension, critically depend on the renal NO systems.FOOTNOTESAddress for reprint requests and other correspondence: P. B. Persson, Johannes-Müller Institut für Physiologie, Tucholskystr. 2, 10117 Berlin (E-mail:pontus.[email protected]de).10.1152/ajpregu.00445.2002REFERENCES1 Abram SR, Alexander BT, Bennett WA, Granger JP.Role of neuronal nitric oxide synthase in mediating renal hemodynamic changes during pregnancy.Am J Physiol Regul Integr Comp Physiol2812001R1390R1393Link | ISI | Google Scholar2 Bastron RD, Kaloyanides GJ.Effect of sodium nitroprusside on function in the isolated and intact dog kidney.J Pharmacol Exp Ther1811972244249PubMed | ISI | Google Scholar3 Brooks VL, Clow KA, Welch LS, Giraud GD.Does nitric oxide contribute to the basal vasodilation of pregnancy in conscious rabbits?Am J Physiol Regul Integr Comp Physiol2812001R1624R1632Link | ISI | Google Scholar4 Cases A, Haas J, Burnett JC, Romero JC.Hemodynamic and renal effects of acute and progressive nitric oxide synthesis inhibition in anesthetized dogs.Am J Physiol Regul Integr Comp Physiol2802001R143R148Link | ISI | Google Scholar5 Chiu T, Reid IA.Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion.J Pharmacol Exp Ther2781996793799PubMed | ISI | Google Scholar6 Conesa EL, Valero F, Nadal JC, Fenoy FJ, Lopez B, Arregui B, Salom MG.N-acetyl-l-cysteine improves renal medullary hypoperfusion in acute renal failure.Am J Physiol Regul Integr Comp Physiol2812001R730R737Link | ISI | Google Scholar7 Cook JL, Zhang Y, Davidge ST.Vascular function in alcohol-treated pregnant and nonpregnant mice.Am J Physiol Regul Integr Comp Physiol2812001R1449R1455Link | ISI | Google Scholar8 Cowley AWLong-term control of arterial blood pressure.Physiol Rev721992231300Link | ISI | Google Scholar9 Danielson LA, Kercher LJ, Conrad KP.Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats.Am J Physiol Regul Integr Comp Physiol2792000R1298R1304Link | ISI | Google Scholar10 DiBona GF.Neural control of the kidney: functionally specific renal sympathetic nerve fibers.Am J Physiol Regul Integr Comp Physiol2792000R1517R1524Link | ISI | Google Scholar11 DiBona GF, Kopp UC.Neural control of renal function.Physiol Rev77199775197Link | ISI | Google Scholar12 Dukacz SA, Feng MG, Yang LF, Lee RM, Kline RL.Abnormal renal medullary response to angiotensin II in SHR is corrected by long-term enalapril treatment.Am J Physiol Regul Integr Comp Physiol2802001R1076R1084Link | ISI | Google Scholar13 Feng MG, Dukacz SA, Kline RL.Selective effect of tempol on renal medullary hemodynamics in spontaneously hypertensive rats.Am J Physiol Regul Integr Comp Physiol2812001R1420R1425Link | ISI | Google Scholar14 Furchgott RF, Zawadzki V.The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature2881980373376Crossref | PubMed | ISI | Google Scholar15 Gandley RE, Conrad KP, McLaughlin MK.Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats.Am J Physiol Regul Integr Comp Physiol2802001R1R7Link | ISI | Google Scholar16 Hefler LA, Tempfer CB, Moreno RM, O'Brien WE, Gregg AR.Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy.Am J Physiol Regul Integr Comp Physiol2802001R174R182Link | ISI | Google Scholar17 Hercule HC, Oyekan AO.Role of NO and cytochrome P-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats.Am J Physiol Regul Integr Comp Physiol2792000R2132R2141Link | ISI | Google Scholar18 Janssen BJ, Leenders PJ, Smits JF.Short-term and long-term blood pressure and heart rate variability in the mouse.Am J Physiol Regul Integr Comp Physiol2782000R215R225Link | ISI | Google Scholar19 Kakoki M, Zou AP, Mattson DL.The influence of nitric oxide synthase 1 on blood flow and interstitial nitric oxide in the kidney.Am J Physiol Regul Integr Comp Physiol2812001R91R97Link | ISI | Google Scholar20 Kanashiro CA, Cockrell KL, Alexander BT, Granger JP, Khalil RA.Pregnancy-associated reduction in vascular protein kinase C activity rebounds during inhibition of NO synthesis.Am J Physiol Regul Integr Comp Physiol2782000R295R303Link | ISI | Google Scholar21 Kopp UC, Cicha MZ, Smith LA, Hokfelt T.Nitric oxide modulates renal sensory nerve fibers by mechanisms related to substance P receptor activation.Am J Physiol Regul Integr Comp Physiol2812001R279R290Link | ISI | Google Scholar22 Kopp UC, Farley DM, Cicha MZ, Smith LA.Activation of renal mechanosensitive neurons involves bradykinin, protein kinase C, PGE2, and substance P.Am J Physiol Regul Integr Comp Physiol2782000R937R946Link | ISI | Google Scholar23 Kurtz A, Wagner C.Cellular control of renin secretion.J Exp Biol2021999219225Crossref | PubMed | ISI | Google Scholar24 Leonard BL, Malpas SC, Denton KM, Madden AC, Evans RG.Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity.Am J Physiol Regul Integr Comp Physiol2802001R62R68Link | ISI | Google Scholar25 Liang M, Knox FG.Production and functional roles of nitric oxide in the proximal tubule.Am J Physiol Regul Integr Comp Physiol2782000R1117R1124Link | ISI | Google Scholar26 Llinas MT, Rodriguez F, Moreno C, Salazar FJ.Role of cyclooxygenase-2-derived metabolites and nitric oxide in regulating renal function.Am J Physiol Regul Integr Comp Physiol2792000R1641R1646Link | ISI | Google Scholar27 Lohmeier TE, Lohmeier JR, Reckelhoff JF, Hildebrandt DA.Sustained influence of the renal nerves to attenuate sodium retention in angiotensin hypertension.Am J Physiol Regul Integr Comp Physiol2812001R434R443Link | ISI | Google Scholar28 Mattson DL, Higgins DJ.Influence of dietary sodium intake on renal medullary nitric oxide synthase.Hypertension271996688692Crossref | PubMed | ISI | Google Scholar29 Menegaz RG, Kapusta DR, Mauad H, de Melo CA.Activation of α2-receptors in the rostral ventrolateral medulla evokes natriuresis by a renal nerve mechanism.Am J Physiol Regul Integr Comp Physiol2812001R98R107Link | ISI | Google Scholar30 Murphy JG, Fleming JB, Cockrell KL, Granger JP, Khalil RA.[Ca2+]i signaling in renal arterial smooth muscle cells of pregnant rat is enhanced during inhibition of NOS.Am J Physiol Regul Integr Comp Physiol2802001R87R99Link | ISI | Google Scholar31 Ollerstam A, Pittner J, Persson AE, Thorup C.Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase.J Clin Invest99199722122218Crossref | PubMed | ISI | Google Scholar32 Peterson TV, Emmeluth C, Bie P.Renal effects of nitric oxide synthase inhibition in conscious water-loaded dogs.Am J Physiol Regul Integr Comp Physiol2812001R584R590Link | ISI | Google Scholar33 Ramirez RJ, Novak J, Johnston TP, Gandley RE, McLaughlin MK, Hubel CA.Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats.Am J Physiol Regul Integr Comp Physiol2812001R1330R1337Link | ISI | Google Scholar34 Rosnes JS, Valego N, Wang JJ, Perez FM, Rose JC.Renin mRNA response to reduced perfusion pressure conserved despite denervation in mature ovine fetuses.Am J Physiol Regul Integr Comp Physiol2802001R1830R1836Link | ISI | Google Scholar35 Sayago CM, Beierwaltes WH.Nitric oxide synthase and cGMP-mediated stimulation of renin secretion.Am J Physiol Regul Integr Comp Physiol2812001R1146R1151Link | ISI | Google Scholar36 Solhaug MJ, Dong XQ, Adelman RD, Dong KW.Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney.Am J Physiol Regul Integr Comp Physiol2782000R1453R1459Link | ISI | Google Scholar37 Solhaug MJ, Kullaprawithaya U, Dong XQ, Dong KW.Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney.Am J Physiol Regul Integr Comp Physiol2802001R1269R1275Link | ISI | Google Scholar38 Stocker SD, Sved AF, Stricker EM.Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine.Am J Physiol Regul Integr Comp Physiol2792000R576R585Link | ISI | Google Scholar39 Stulak JM, Juncos LA, Haas JA, Romero JC.Systemic hemodynamics and renal function in hemorrhaged dogs resuscitated with cross-linked hemoglobin.Am J Physiol Regul Integr Comp Physiol2782000R28R33Link | ISI | Google Scholar40 Valdivielso JM, Crespo C, Alonso JR, Martinez-Salgado C, Eleno N, Arevalo M, Perez-Barriocanal F, Lopez-Novoa JM.Renal ischemia in the rat stimulates glomerular nitric oxide synthesis.Am J Physiol Regul Integr Comp Physiol2802001R771R779Link | ISI | Google Scholar41 Yang ZW, Gebrewold A, Nowakowski M, Altura BT, Altura BM.Mg2+-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO.Am J Physiol Regul Integr Comp Physiol2782000R628R639Link | ISI | Google Scholar42 Zou AP, Cowley AW.α2-Adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction.Am J Physiol Regul Integr Comp Physiol2792000R769R777Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByTagetes erecta L. flowers, a medicinal plant traditionally used to promote diuresis, induced diuretic and natriuretic effects in normotensive and hypertensive ratsJournal of Ethnopharmacology, Vol. 279Effects of myricetin-3- O -α-rhamnoside (myricitrin) treatment on urinary parameters of Wistar rats6 October 2019 | Journal of Pharmacy and Pharmacology, Vol. 71, No. 12Aerobic training and L-arginine supplement attenuates myocardial infarction-induced kidney and liver injury in rats via reduced oxidative stressIndian Heart Journal, Vol. 70, No. 4Sustained resveratrol infusion increases natriuresis independent of renal vasodilation11 September 2014 | Physiological Reports, Vol. 2, No. 9Development of Renal Function in the Fetus and Newborn15 October 2013Autonomic control of the urogenital tractAutonomic Neuroscience, Vol. 165, No. 1Prevention of Renal Injury and Endothelial Dysfunction by Chronic l -Arginine and Antioxidant Treatment10 January 2011 | Renal Failure, Vol. 33, No. 1Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats25 September 2009 | International Urology and Nephrology, Vol. 42, No. 3Upregulation of renal eNOS by high-sodium diet facilitates hypertension in doxorubicin-treated rats through enhanced oxidative stressToxicology, Vol. 225, No. 2-3Decrease in tetrahydrobiopterin as a possible cause of nephropathy in type II diabetic ratsKidney International, Vol. 70, No. 3Asymmetric dimethylarginine: a new player in the pathogenesis of renal disease?Current Opinion in Nephrology and Hypertension, Vol. 15, No. 3Asymmetric dimethylarginine (ADMA): a cardiovascular and renal risk factor on the moveJournal of Hypertension, Vol. 24, No. 4Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension?Christopher S. Wilcox11 October 2005 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 289, No. 4Assessment of the nitric oxide system in the heart, aorta and kidney of aged Wistar–Kyoto and spontaneously hypertensive ratsJournal of Hypertension, Vol. 23, No. 8Recent Advances in the Regulation of Nitric Oxide in the KidneyHypertension, Vol. 45, No. 6Renal endothelial effects of antihypertensive therapyCurrent Opinion in Nephrology and Hypertension, Vol. 13, No. 5Functional Development of the Kidney In UteroKidney adaptation in nitric oxide-deficient Wistar and spontaneously hypertensive ratsLife Sciences, Vol. 74, No. 11Emerging drugs for renal failure2 March 2005 | Expert Opinion on Emerging Drugs, Vol. 8, No. 2Opening of Mitochondrial ATP-Sensitive Potassium Channels Is a Trigger of 3-Nitropropionic Acid–Induced Tolerance to Transient Focal Cerebral Ischemia in RatsStroke, Vol. 34, No. 4 More from this issue > Volume 283Issue 5November 2002Pages R1005-R1007 Copyright & PermissionsCopyright © 2002 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00445.2002PubMed12376391History Published online 1 November 2002 Published in print 1 November 2002 Metrics