Abstract-The Notch3 receptor participates in the development and maturation of vessels. Mutations of Notch3 in humans are associated with defective regulation of cerebral blood flow. To investigate the role of Notch3 in the regulation of renal hemodynamics, we used mice lacking expression of the Notch3 gene (Notch3Ϫ/Ϫ mice). Bolus injections of norepinephrine and angiotensin II increased renal vascular resistance and decreased renal blood flow in a dose-dependent manner in wild-type mice. In sharp contrast, renal vascular resistance of Notch3Ϫ/Ϫ mice varied little after boluses of norepinephrine and angiotensin II. Inversely, bradykinin and prostacyclin relaxed renal vasculature in wild-type mice. Both vasodilators had a negligible effect on renal vascular resistance of Notch3Ϫ/Ϫ mice. Afferent arterioles freshly isolated from Notch3Ϫ/Ϫ mice displayed decreased thickness of vascular wall compared with wild -type mice and showed a deficient contractile response to angiotensin II. To examine the physiopathological consequences of the above-described deficiency, hypertension was induced by continuous infusion of angiotensin II. Angiotensin II gradually increased blood pressure in both strains, but this increase was lesser in the Notch3Ϫ/Ϫ mice. Despite this blunted systemic effect, Notch3Ϫ/Ϫ mice displayed high mortality rates (65%) attributed to heart failure. In the kidney, the surviving Notch3Ϫ/Ϫ mice showed focal structural alterations characteristic of nephroangiosclerosis. These data show that Notch3 is necessary for the adaptive response of the renal vasculature to vasoactive systems. A deficiency in the expression of Notch3 could have important physiopathological consequences in the adaptation of the cardiac and renal function to chronic increase of blood pressure.
, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca i 2ϩ ) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140 -F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10 Ϫ7 mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME). In AAs from the nonclipped kidney, L-NAME increased the ANG II-induced Ca i 2ϩ response from 0.28 Ϯ 0.05 to 0.55 Ϯ 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 Ϯ 6 to 60 Ϯ 6% of baseline (P Ͻ 0.05). In vessels from sham and clipped kidneys, L-NAME had no effect. In diaminofluorescein-FM diacetateloaded AAs from the nonclipped kidney, ANG II increased NOderived fluorescence to 145 Ϯ 34% of baseline (P Ͻ 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of L-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca i 2ϩ and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.two-kidney; one-clip; renovascular hypertension TWO-KIDNEY, ONE-CLIP (2K1C) has been studied as an ANG II-dependent model of renovascular hypertension. Earlier studies have demonstrated elevated circulating levels of ANG II, with high ANG II concentration in the cortical tissue of the clipped and nonclipped kidney (20).Renal blood flow (RBF) and intrarenal vascular resistance are controlled by autocrine and paracrine factors as well as myogenic and tubuloglomerular feedback responses. The afferent arteriole (AA) is the main site for RBF and glomerular filtration rate (GFR) regulation and plays an important role during development of 2K1C hypertension (12). The clipped kidney has reduced RBF and GFR (18), impaired autoregulation, and dilated AAs (14). Although RBF autoregulation is reset to higher perfusion pressures, the nonclipped kidney has well-maintained RBF and GFR (6) despite high levels of circulating and cortical tissue ANG II.Previously, we found that the ANG II dose-response curve in AAs from clipped kidneys did not saturate at high doses (10 Ϫ6 M), while those from sham and nonclipped kidneys did (5). The effect of cyclooxygenase (COX) inhibition, together with mRNA and protein (1) expression for the AT 1a receptor, was similar in the nonclipped and clipped kidneys. This indicated that the changed dose-response relationship was...
Our data demonstrate significantly increased hormonal vasoreactivity of skin vessels from rats on a high-salt diet, which could increase peripheral resistance in many situations and contribute to higher pressure in salt-sensitive hypertension. As vessels from adjacent muscle were unaffected, we raise the interesting possibility that increased vasoreactivity in the skin could be linked to osmotically inactive Na(+) accumulation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.