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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Albuminuria amelioratesISOShc1 (Rattus norvegicus)12792230; 12792230compared to SS/JrHsdMcwiRGD 
Albuminuria amelioratesIMP 12792230compared to SS/JrHsdMcwiRGD 
Albuminuria amelioratesIAGP 12792230 RGD 
Albuminuria amelioratesIMP 12792230; 12792230 RGD 
glomerulosclerosis amelioratesISOShc1 (Rattus norvegicus)12792230; 12792230compared to SS/JrHsdMcwiRGD 
glomerulosclerosis amelioratesIMP 12792230compared to SS/JrHsdMcwiRGD 
glomerulosclerosis amelioratesIAGP 12792230compared to SS/JrHsdMcwiRGD 
glomerulosclerosis amelioratesIMP 12792230; 12792230 RGD 
Hypertensive Nephropathy  ISOShc1 (Rattus norvegicus)12792230; 12792230protein:increased expression:kidneyRGD 
Hypertensive Nephropathy inducedIMPcontrolled sodium content diet12792230 RGD 
Hypertensive Nephropathy MODEL: inducedIAGPcontrolled sodium content diet12792230 RGD 
Hypertensive Nephropathy  IEP 12792230protein:increased expression:kidneyRGD 
Hypertensive Nephropathy  IMP 12792230; 12792230 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of smooth muscle contraction  IMP 12792230 RGD 
response to endothelin  IMP 12792230 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased tubuloglomerular feedback response  IMP 12792230compared to SS-Chr 2BN/Mcwi more ...RGD 
decreased tubuloglomerular feedback response  IAGP 12792230compared to SS-Chr 2BN/Mcwi more ...RGD 
decreased tubuloglomerular feedback response  IMP 12792230; 12792230 RGD 
decreased urine albumin level  IMP 12792230compared to SS/JrHsdMcwiRGD 
decreased urine albumin level  IAGP 12792230compared to SS/JrHsdMcwiRGD 
decreased urine albumin level  IMP 12792230; 12792230 RGD 
glomerulosclerosis amelioratesIMP 12792230compared to SS/JrHsdMcwiRGD 
glomerulosclerosis amelioratesIAGP 12792230compared to SS/JrHsdMcwiRGD 
glomerulosclerosis amelioratesIMP 12792230; 12792230 RGD 
increased vasoconstriction inducedIMPAdenosine triphosphate and controlled sodium content diet12792230; 12792230compared to SS/JrHsdMcwi and SS-Shc1em5McwiRGD 
increased vasoconstriction inducedIMPcontrolled sodium content diet and endothelin-112792230compared to SS-Shc1em5McwiRGD 
increased vasoconstriction inducedIAGPAdenosine triphosphate and controlled sodium content diet12792230compared to SS/JrHsdMcwi and SS-Shc1em5McwiRGD 
increased vasoconstriction inducedIAGPcontrolled sodium content diet and endothelin-112792230; 12792230compared to SS-Shc1em5McwiRGD 
increased vasoconstriction  IMP 12792230; 12792230; 12792230 RGD 

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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