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p66Shc regulates renal vascular tone in hypertension-induced nephropathy. J Clin Invest 2016 07 01;126(7):2533-46

Date

06/09/2016

Pubmed ID

27270176

Pubmed Central ID

PMC4922697

DOI

10.1172/JCI75079

Scopus ID

2-s2.0-84978419542   9 Citations

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.

Author List

Miller B, Palygin O, Rufanova VA, Chong A, Lazar J, Jacob HJ, Mattson D, Roman RJ, Williams JM, Cowley AW Jr, Geurts AM, Staruschenko A, Imig JD, Sorokin A

Authors

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
John D. Imig PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Oleg Palygin PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin
Alexander V. Staruschenko PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Albumins
Animals
Arterioles
Blood Pressure
Calcium
Hypertension
Hypertension, Renal
Kidney
Kidney Glomerulus
Male
Microcirculation
Muscle, Smooth, Vascular
Nephritis
Promoter Regions, Genetic
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Rats, Inbred WKY
Rats, Transgenic
Species Specificity
Src Homology 2 Domain-Containing, Transforming Protein 1
Vasoconstriction
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc