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 9

p66Shc actions mediate effect of ET-1 on TRPC channel activity.

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p66Shc actions mediate effect of ET-1 on TRPC channel activity. (A) Repr...
(A) Representative single-channel traces on vascular SMCs before and after ET-1 treatment in cells derived from WT, M1, and Ser36Ala rats. All traces were recorded at –80 mV holding potential. Insets show 10-second single-channel recording intervals. (B) Point-wise comparison of means of single-channel amplitude changes after ET-1 application. Each curve represents the sum of 7 independent experiments. (C) ET-1 (100 nM) induces changes in TRPC channel activity (NPo). M1 is significantly different from WT or Ser36Ala (#P < 0.05). WT significance difference with Ser36Ala is also shown (*P < 0.05). (D) Changes in current density J, pA/s calculated as total current integral ratio to the first 100 seconds after activation start point. Ser36Ala significantly differs from WT. M1 significant increase versus WT or Ser36Ala is indicated. *P < 0.05. Striped bars represent control value before ET-1 application. All summarized data are reported as mean ± SEM. Data from before and after treatment within the same experiment were compared using the paired t test. Data from different experiments were compared with a Student’s t test (2 tailed) or 1-way ANOVA as appropriate.