p66Shc regulates renal vascular tone in Hypertension-induced nephropathy

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, Aron M. Geurts, Alexander Staruschenko, John D. Imig, Andrey Sorokin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2533-2546
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

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Blood Vessels
Hypertension
Kidney
Arterioles
Smooth Muscle Myocytes
Mutant Strains Rats
Salts
Inbred Dahl Rats
Transient Receptor Potential Channels
Microcirculation
Vascular Smooth Muscle
Proteins
Pressure

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Miller, B., Palygin, O., Rufanova, V. A., Chong, A., Lazar, J., Jacob, H. J., ... Sorokin, A. (2016). p66Shc regulates renal vascular tone in Hypertension-induced nephropathy. Journal of Clinical Investigation, 126(7), 2533-2546. https://doi.org/10.1172/JCI75079

p66Shc regulates renal vascular tone in Hypertension-induced nephropathy. / Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A.; Chong, Andrew; Lazar, Jozef; Jacob, Howard J.; Mattson, David; Roman, Richard J.; Williams, Jan M.; Cowley, Allen W.; Geurts, Aron M.; Staruschenko, Alexander; Imig, John D.; Sorokin, Andrey.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2533-2546.

Research output: Contribution to journalArticle

Miller, B, Palygin, O, Rufanova, VA, Chong, A, Lazar, J, Jacob, HJ, Mattson, D, Roman, RJ, Williams, JM, Cowley, AW, Geurts, AM, Staruschenko, A, Imig, JD & Sorokin, A 2016, 'p66Shc regulates renal vascular tone in Hypertension-induced nephropathy', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2533-2546. https://doi.org/10.1172/JCI75079
Miller B, Palygin O, Rufanova VA, Chong A, Lazar J, Jacob HJ et al. p66Shc regulates renal vascular tone in Hypertension-induced nephropathy. Journal of Clinical Investigation. 2016 Jul 1;126(7):2533-2546. https://doi.org/10.1172/JCI75079
Miller, Bradley ; Palygin, Oleg ; Rufanova, Victoriya A. ; Chong, Andrew ; Lazar, Jozef ; Jacob, Howard J. ; Mattson, David ; Roman, Richard J. ; Williams, Jan M. ; Cowley, Allen W. ; Geurts, Aron M. ; Staruschenko, Alexander ; Imig, John D. ; Sorokin, Andrey. / p66Shc regulates renal vascular tone in Hypertension-induced nephropathy. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2533-2546.
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