RGD Reference Report - Tempol reduces oxidative stress and restores renal dopamine D1-like receptor- G protein coupling and function in hyperglycemic rats. - Rat Genome Database

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Tempol reduces oxidative stress and restores renal dopamine D1-like receptor- G protein coupling and function in hyperglycemic rats.

Authors: Marwaha, A  Lokhandwala, MF 
Citation: Marwaha A and Lokhandwala MF, Am J Physiol Renal Physiol. 2006 Jul;291(1):F58-66. Epub 2006 Feb 14.
RGD ID: 1625789
Pubmed: PMID:16478977   (View Abstract at PubMed)
DOI: DOI:10.1152/ajprenal.00362.2005   (Journal Full-text)

Dopamine via activation of renal D1-like receptors inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with hyperglycemic conditions. We have earlier reported D1-like receptor-G protein uncoupling and reduced response to D1-like receptor activation in streptozotocin (STZ)-treated hyperglycemic rats (Marwaha A, Banday AA, and Lokhandwala MF. Am J Physiol Renal Physiol 286: F451-F457, 2004). The present study was designed to test the hypothesis that oxidative stress associated with hyperglycemia increases basal D1-like receptor serine phosphorylation via activation of the PKC-G protein receptor kinase (GRK) pathway, resulting in loss of D1-like receptor-G protein coupling and function. We observed that STZ-treated rats exhibited oxidative stress as evidenced by increased lipid peroxidation. Furthermore, PKC activity and expression of PKC-betaI- and -delta-isoforms were increased in STZ-treated rats. In addition, in STZ-treated rats there was increased GRK2 translocation to proximal tubular membrane and increased basal serine D1-like receptor phosphorylation. Supplementation with the antioxidant tempol lowered oxidative stress in STZ-treated rats, led to normalization of PKC activity, and prevented GRK2 translocation. Furthermore, tempol supplementation in STZ-treated rats restored D1-like receptor-G protein coupling and inhibition of Na-K-ATPase activity on D1-like receptor agonist stimulation. The functional consequence was the restoration of the natriuretic response to D1-like receptor activation. We conclude that oxidative stress associated with hyperglycemia causes an increase in activity and expression of PKC. This leads to translocation of GRK2, subsequent phosphorylation of the D1-like receptor, its uncoupling from G proteins and loss of responsiveness to agonist stimulation.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GRK2Humanhyperglycemia  ISOGrk2 (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 
Grk2Rathyperglycemia  IDA associated with Diabetes Mellitus and ExperimentalRGD 
Grk2Mousehyperglycemia  ISOGrk2 (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Grk2Ratresponse to oxidative stress  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Mus musculus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Homo sapiens)
GRK2  (G protein-coupled receptor kinase 2)


Additional Information