p66Shc regulates renal vascular tone in hypertension-induced nephropathy.
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.
Bradley
B
Miller
Oleg
O
Palygin
Victoriya A
VA
Rufanova
Andrew
A
Chong
Jozef
J
Lazar
Howard J
HJ
Jacob
David
D
Mattson
Richard J
RJ
Roman
Jan M
JM
Williams
Allen W
AW
Cowley
Aron M
AM
Geurts
Alexander
A
Staruschenko
John D
JD
Imig
Andrey
A
Sorokin
D000418:Albumins / Q000032:analysis; D000818:Animals; D001160:Arterioles / Q000503:physiopathology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology; D006977:Hypertension, Renal / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009393:Nephritis / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D011921:Rats, Inbred WKY; D055647:Rats, Transgenic; D013045:Species Specificity; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000378:metabolism*; D014661:Vasoconstriction
D000418:Albumins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D002118:Calcium