RGD Reference Report - p66Shc regulates renal vascular tone in hypertension-induced nephropathy. - Rat Genome Database

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p66Shc regulates renal vascular tone in hypertension-induced nephropathy.

Authors: 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 
Citation: Miller B, etal., J Clin Invest. 2016 Jul 1;126(7):2533-46. doi: 10.1172/JCI75079. Epub 2016 Jun 6.
RGD ID: 12792230
Pubmed: PMID:27270176   (View Abstract at PubMed)
PMCID: PMC4922697   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI75079   (Journal Full-text)

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.

Disease Annotations    
Albuminuria  (IAGP,IMP,ISO)
glomerulosclerosis  (IAGP,IMP,ISO)
Hypertensive Nephropathy  (IAGP,IEP,IMP,ISO)

Gene Ontology Annotations    

Biological Process

Phenotype Annotations    

Mammalian Phenotype

Phenotype Values via PhenoMiner     Click to see Annotation Detail View
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Strains with Phenominer Data Strains with phenominer data
SS/JrHsdMcwi SS-Chr 2BN/Mcwi SS-Shc1em1Mcwi
SS-Shc1em4Mcwi SS-Shc1em5Mcwi

Objects Annotated

Genes (Rattus norvegicus)
Shc1  (SHC adaptor protein 1)
Shc1em1Mcwi  (SHC adaptor protein 1; ZFN induced mutant 1, Medical College of Wisconsin)
Shc1em4Mcwi  (SHC adaptor protein 1; ZFN induced mutant 4, Medical College of Wisconsin)
Shc1em5Mcwi  (SHC adaptor protein 1; ZFN induced mutant 5, Medical College of Wisconsin)

Genes (Mus musculus)
Shc1  (src homology 2 domain-containing transforming protein C1)

Genes (Homo sapiens)
SHC1  (SHC adaptor protein 1)

Additional Information