p66Shc regulates renal vascular tone in hypertension-induced nephropathy
Bradley Miller, … , John D. Imig, Andrey Sorokin
Bradley Miller, … , John D. Imig, Andrey Sorokin
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2533-2546. https://doi.org/10.1172/JCI75079.
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Research Article Nephrology Vascular biology

p66Shc regulates renal vascular tone in hypertension-induced nephropathy

Abstract

Renal preglomerular arterioles regulate vascular tone to ensure a large pressure gradient over short distances, a function that is extremely important for maintaining renal microcirculation. Regulation of renal microvascular tone is impaired in salt-sensitive (SS) hypertension–induced nephropathy, but the molecular mechanisms contributing to this impairment remain elusive. Here, we assessed the contribution of the SH2 adaptor protein p66Shc (encoded by Shc1) in regulating renal vascular tone and the development of renal vascular dysfunction associated with hypertension-induced nephropathy. We generated a panel of mutant rat strains in which specific modifications of Shc1 were introduced into the Dahl SS rats. In SS rats, overexpression of p66Shc was linked to increased renal damage. Conversely, deletion of p66Shc from these rats restored the myogenic responsiveness of renal preglomerular arterioles ex vivo and promoted cellular contraction in primary vascular smooth muscle cells (SMCs) that were isolated from renal vessels. In primary SMCs, p66Shc restricted the activation of transient receptor potential cation channels to attenuate cytosolic Ca2+ influx, implicating a mechanism by which overexpression of p66Shc impairs renal vascular reactivity. These results establish the adaptor protein p66Shc as a regulator of renal vascular tone and a driver of impaired renal vascular function in hypertension-induced nephropathy.

Authors

Bradley Miller, Oleg Palygin, Victoriya A. Rufanova, Andrew Chong, Jozef Lazar, Howard J. Jacob, David Mattson, Richard J. Roman, Jan M. Williams, Allen W. Cowley Jr., Aron M. Geurts, Alexander Staruschenko, John D. Imig, Andrey Sorokin

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Figure 1

Dahl SS and SS/BN2 consomic rats respond differently to a 1% salt diet.

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Dahl SS and SS/BN2 consomic rats respond differently to a 1% salt diet. ...
(A) Survival of male SS and SS/BN2 consomic rats when fed a 1% salt diet. (B) Light microscopy of renal cortical sections after Masson’s trichrome staining demonstrates the development of renal pathologies in age-matched SS (upper panel) and SS/BN2 (lower panel) rats. Rats were 34-week-old males. Scale bars: 100 μm. (C) Renal microvascular responses to purinergic activation are impaired in SS rats kept on a 1% salt diet. Responses of interlobular renal arterioles to ATP were compared in SS rats and SS/BN2 rats fed a 1% salt diet. Rats were 15- to 19-week-old males. Statistical comparisons within each series were made using 1-way ANOVA for repeated measures combined with the Newman-Keuls multiple range test. Comparisons between groups were made using 1-way ANOVA with the Newman–Keuls multiple range test. A probability value of P < 0.05 was considered statistically significant. All data are reported as mean ± SEM.