Role of Thioredoxin 1 in Impaired Renal Sodium Excretion of hD5RF173L Transgenic Mice

Background Dopamine D5 receptor (D5R) plays an important role in the maintenance of blood pressure by regulating renal sodium transport. Our previous study found that human D5R mutant F173L transgenic (hD5RF173L‐TG) mice are hypertensive. In the present study, we aimed to investigate the mechanisms causing this renal D5R dysfunction in hD5RF173L‐TG mice. Methods and Results Compared with wild‐type D5R‐TG (hD5RWT‐TG) mice, hD5RF173L‐TG mice have higher blood pressure, lower basal urine flow and sodium excretion, and impaired agonist‐mediated natriuresis and diuresis. Enhanced reactive oxygen species production in hD5RF173L‐TG mice is caused, in part, by decreased expression of antioxidant enzymes, including thioredoxin 1 (Trx1). Na+‐K+‐ATPase activity is increased in mouse renal proximal tubule cells transfected with hD5RF173L, but is normalized by treatment with exogenous recombinant human Trx1 protein. Regulation of Trx1 by D5R occurs by the phospholipase C/ protein kinase C (PKC) pathway because upregulation of Trx1 expression by D5R does not occur in renal proximal tubule cells from D1R knockout mice in the presence of a phospholipase C or PKC inhibitor. Fenoldopam, a D1R and D5R agonist, stimulates PKC activity in primary renal proximal tubule cells of hD5RWT‐TG mice, but not in those of hD5RF173L‐TG mice. Hyperphosphorylation of hD5RF173L and its dissociation from Gαs and Gαq are associated with impairment of D5R‐mediated inhibition of Na+‐K+‐ATPase activity in hD5RF173L‐TG mice. Conclusions These suggest that hD5RF173L increases blood pressure, in part, by decreasing renal Trx1 expression and increasing reactive oxygen species production. Hyperphosphorylation of hD5RF173L, with its dissociation from Gαs and Gαq, is the key factor in impaired D5R function of hD5RF173L‐TG mice.

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