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TRANSLATIONAL PHYSIOLOGY

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

Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas

Submitted 7 September 2005 ; accepted in final form 8 February 2006

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-I- and --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.

G protein receptor kinases; protein kinase C; antioxidant; streptozotocin; SKF-38393

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