Coordinate changes of renin and brain-type nitric-oxide-synthase (b-NOS) mRNA levels in rat kidneys

Schricker, K. Th.; Pötzl, Bernhard; Hamann, Marlies; Kurtz, Armin

doi:10.1007/s004240050150

Cited by 62 publications

(49 citation statements)

References 34 publications

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“…This question has been of considerable interest because of the striking observation that nNOS, one of the NO-generating enzymes, is expressed at high levels in MD cells and that its level of expression varies in parallel to that of renin in a number of experimental conditions (4,32,43,46,50). For two major reasons, the question of a specific role of nNOS in MDdependent renin release has been difficult to address experimentally.…”

Section: Discussionmentioning

confidence: 99%

“…Reductions in oral salt intake (4,42,46,50), renal hypoperfusion, and pharmacological blockade of Na-K-2Cl cotransport of the thick ascending limb (4,43) all stimulate the expression of both proteins. Furthermore, changes in NOS activity have been demonstrated to affect renin secretion, and the majority of studies suggest a stimulatory role for NO (4,20,35,40,42).…”

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confidence: 99%

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Permissive role of nitric oxide in macula densa control of renin secretion

Castrop

Schweda²,

Mizel³

et al. 2004

American Journal of Physiology-Renal Physiology

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Experiments were performed in neuronal (nNOS)-and endothelial nitric oxide synthase (eNOS)-deficient mice to study the role of nitric oxide (NO) in macula densa control of renin secretion in vivo and in the isolated, perfused mouse kidney. Acute and chronic administration of loop diuretics was used as a method to stimulate macula densa-mediated renin secretion. Increases in plasma renin concentration (PRC) in response to a 3-day infusion of bumetanide (50 mg⅐kg Ϫ1 ⅐day Ϫ1 ) or an acute injection of furosemide (50 mg/kg ip) were not markedly altered in nNOSϪ/Ϫ mice. Responses to furosemide were also maintained in eNOSϪ/Ϫ mice, but the administration of N -nitro-L-arginine methyl ester (L-NAME) markedly attenuated the PRC response to furosemide in these mice. In the isolated kidney preparation, bumetanide caused similar relative increases in renin secretion in kidneys of wild-type, nNOSϪ/Ϫ, and eNOSϪ/Ϫ mice. Bumetanide only marginally increased renin secretion in L-NAME-treated kidneys, but the bumetanide effect was normalized by S-nitroso-N-acetyl-penicillamine. Basal PRC was significantly reduced in male nNOSϪ/Ϫ mice compared with nNOSϩ/ϩ (189 Ϯ 28 vs. 355 Ϯ 57 ng ANG I ⅐ml Ϫ1 ⅐h Ϫ1 ; P ϭ 0.017). There was no significant difference in PRC between eNOSϩ/ϩ and eNOSϪ/Ϫ mice. Basal renin secretion rates in perfused kidneys isolated from nNOSϪ/Ϫ or eNOSϪ/Ϫ mice were markedly reduced compared with wild-type controls. Our data suggest that NO generated by macula densa nNOS does not play a specific mediator role in macula densa-dependent renin secretion. However, NO independent of its exact source permits the macula densa pathway of renin secretion to function normally. plasma renin; isolated, perfused kidney; neuronal nitric oxide synthase knockout; endothelial nitric oxide synthase knockout; furosemide; bumetanide THE MACULA DENSA (MD) CELLS LOCATED at the terminal end of the loop of Henle are believed to play an important role in both the regulation of preglomerular resistance and the control of renin secretion. Commensurate with their distinct function as sensor cells in these local regulatory pathways, MD cells have a number of unique characteristics that distinguish them from neighboring cells of the cortical thick ascending limb. One of the more striking of these discriminating features is the expression of substantial amounts of neuronal nitric oxide synthase (nNOS) and the ability to generate nitric oxide (NO) (31, 53).A considerable body of experimental evidence indicates that the expression of nNOS in the MD and the expression and secretion of renin by juxtaglomerular (JG) granular cells are altered in parallel by a variety of interventions. Reductions in oral salt intake (4,42,46, 50), renal hypoperfusion, and pharmacological blockade of Na-K-2Cl cotransport of the thick ascending limb (4, 43) all stimulate the expression of both proteins. Furthermore, changes in NOS activity have been demonstrated to affect renin secretion, and the majority of studies suggest a stimulatory role for NO (4,20,35,40,42). It ha...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Permissive role of nitric oxide in macula densa control of renin secretion

Castrop

Schweda²,

Mizel³

et al. 2004

American Journal of Physiology-Renal Physiology

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“…In addition, macula densa neuronal NO synthase (nNOS)-mediated NO generation can stimulate renin release (18). The increase in renin release on furosemide reportedly is inhibited in the presence of nonspecific or specific nNOS blockers (137), yet furosemide did not affect renal nNOS gene expression in healthy rats (139). Conversely, furosemide can reduce renin release by increased luminal Na ϩ concentration at the level of the macula densa (105,138).…”

Section: Are Direct Vascular Actions Of Furosemide Important and Whatmentioning

confidence: 99%

Everything we always wanted to know about furosemide but were afraid to ask

Huang

Mees

Vos

et al. 2016

American Journal of Physiology-Renal Physiology

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Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958 -F971, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00476.2015.-Furosemide is a widely used, potent natriuretic drug, which inhibits the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion. extracellular fluid volume; natriuresis; renal function; chronic kidney disease; heart failure DIURETICS BLOCKING THE Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC) have an important place in the treatment of fluid overload, specifically in the context of kidney disease and heart failure (64). Of the drugs that inhibit the NKCC2 in the loop of Henle (furosemide, bumetanide, torsemide, ethacrynic acid), furosemide is most commonly applied (66) and Ͼ40 million prescriptions are dispensed every year in the USA (66a). However, many uncertainties remain about intrarenal and systemic actions of furosemide, including its two main targets NKCC1 and NKCC2.Clinically, there are a number of undesirable consequences of the use of furosemide, of which the pathophysiological mechanisms have not been sufficiently investigated. Furosemide has been associated with worsening of kidney function in patients treated for volume overload admitted for acute heart failure (104) and even glomerular filtration rate (GFR) ...

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“…In the kidney, however, the regulation of eNOS activity under various physiologic conditions is not well understood. Previous experiments testing the effects of altered salt intake or BP on renal eNOS activity have yielded inconsistent results (2)(3)(4)(5)(6)(7)(8). While there is little information on the endogenous factors that regulate eNOS expression within the kidney, angiotensin II (AngII) is regarded as an important candidate for the stimulatory regulator of renal vascular eNOS expression (9,10).…”

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confidence: 99%

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

Satô

Kihara²,

Hashimoto³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The effects of altered dietary salt intake and/or hydralazine-induced hypotension on renal endothelial nitric oxide synthase (eNOS) expression were determined in angiotensin type-1a receptor gene knockout (At1aϪ/Ϫ) and wild-type (At1aϩ/ϩ) mice. In At1aϪ/Ϫ mice, the levels of renal cortical eNOS mRNA and protein were 5 times and 3.5 times higher, respectively, in the high-salt (4% NaCl) group than in the low-salt group (0.3% NaCl). Systemic BP of the high-salt group (105 Ϯ 4.4 mmHg) was significantly higher than that of the low-salt group (77.0 Ϯ 4.7 mmHg). When hydralazine was administered to the mutant mice fed a high-salt diet, BP was reduced to 72.5 Ϯ 1.3 mmHg, with decreases in the levels of renal eNOS mRNA and protein expression to about half of those found in nontreated group. Consistent with the results for eNOS mRNA and protein expression, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity and eNOS immunoreactivity localized in the endothelium of the renal vasculature changed parallel with the amount of salt intake. In contrast to mutant mice, At1aϩ/ϩ mice did not show any changes in renal eNOS expression during the manipulation of salt intake and/or hydralazine-induced hypotension. These results suggest that At1a receptor-mediated inputs play critical roles in maintaining renal vascular eNOS expression and activity during changes in salt-water balance and systemic BP.The endothelial nitric oxide synthase (eNOS) is distributed throughout the renal vasculature, from the renal arterial branches to the glomerular capillaries. NO synthesized by eNOS in response to renal perfusion pressure and the tubuloglomerular feedback system is thought to be an important modulator of vascular tone. Renal perfusion pressure has been shown to increase urinary NO 2 /NO 3 excretion as well as output current from an electrode inserted into the renal cortex (1).eNOS is a constitutively expressed enzyme responsible for the generation of basal NO release from endothelial cells. The major stimuli of enzyme activity include shear stress and/or pressure stretch. In the kidney, however, the regulation of eNOS activity under various physiologic conditions is not well understood. Previous experiments testing the effects of altered salt intake or BP on renal eNOS activity have yielded inconsistent results (2-8).While there is little information on the endogenous factors that regulate eNOS expression within the kidney, angiotensin II

show abstract

Coordinate changes of renin and brain-type nitric-oxide-synthase (b-NOS) mRNA levels in rat kidneys

Cited by 62 publications

References 34 publications

Permissive role of nitric oxide in macula densa control of renin secretion

Permissive role of nitric oxide in macula densa control of renin secretion

Everything we always wanted to know about furosemide but were afraid to ask

Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type-1a Receptor Gene Knockout Mice

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