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.