Abstract
Nitric oxide (NO) modulates renal blood flow (RBF) and kidney function and is involved in blood pressure (BP) regulation predominantly via stimulation of the NO-sensitive guanylyl cyclase (NO-GC), existing in two isoforms, NO-GC1 and NO-GC2. Here, we used isoform-specific knockout (KO) mice and investigated their contribution to renal hemodynamics under normotensive and angiotensin II-induced hypertensive conditions. Stimulation of the NO-GCs by S-nitrosoglutathione (GSNO) reduced BP in normotensive and hypertensive wildtype (WT) and NO-GC2-KO mice more efficiently than in NO-GC1-KO. NO-induced increase of RBF in normotensive mice did not differ between the genotypes, but the respective increase under hypertensive conditions was impaired in NO-GC1-KO. Similarly, inhibition of endogenous NO increased BP and reduced RBF to a lesser extent in NO-GC1-KO than in NO-GC2-KO. These findings indicate NO-GC1 as a target of NO to normalize RBF in hypertension. As these effects were not completely abolished in NO-GC1-KO and renal cyclic guanosine monophosphate (cGMP) levels were decreased in both NO-GC1-KO and NO-GC2-KO, the results suggest an additional contribution of NO-GC2. Hence, NO-GC1 plays a predominant role in the regulation of BP and RBF, especially in hypertension. However, renal NO-GC2 appears to compensate the loss of NO-GC1, and is able to regulate renal hemodynamics under physiological conditions.
Highlights
To ensure renal function, renal blood flow (RBF) is kept constant during a wide range of systemic blood pressure levels due to adjustment of renal vascular resistance
In order to get more insights into how the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway regulates renal hemodynamics, we investigated the relative contribution of the NO-GC1 and NO-GC2 isoforms on renal blood flow, renal vascular function, and blood pressure regulation by using NO-GC1-KO and NO-GC2-KO mice
In order to investigate the impact of NO-sensitive guanylyl cyclase (NO-GC) isoforms on renal hemodynamics, we measured renal blood flow in unconscious WT, NO-GC1-KO, and NO-GC2-KO mice
Summary
Renal blood flow (RBF) is kept constant during a wide range of systemic blood pressure levels due to adjustment of renal vascular resistance. Additional deletion of NO-GC2 in smooth muscle cells resulted in hypertension by reducing vascular responsiveness to NO, which confirms the importance of NO-GC2 as a target for endothelial NO in the systemic vasculature [10]. Deficiency of NO causes dysfunction of renal blood flow and promotes renal failure and hypertension [15] In this context, a recent study has shown that activation of NO-GC by cinaciguat under NO-deficient conditions can normalize blood pressure and reduce renal vasoconstriction to improve renal blood flow autoregulation [16]. In order to get more insights into how the NO/cGMP pathway regulates renal hemodynamics, we investigated the relative contribution of the NO-GC1 and NO-GC2 isoforms on renal blood flow, renal vascular function, and blood pressure regulation by using NO-GC1-KO and NO-GC2-KO mice
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