Role of Thioredoxin 1 in Impaired Renal Sodium Excretion of hD 5 R F173L Transgenic Mice

作者：Shaoxiong Wang, Xiaorong Tan, Peng Chen, Shuo Zheng, Hongmei Ren, Jin Cai, Lin Zhou, Pedro A. José, Jian Yang, Chunyu Zeng · 发表于：Journal of the American Heart Association · 年份：2019 · DOI：10.1161/jaha.119.012192 · 被引用次数：15 · 研究领域：Renin-Angiotensin System Studies、Hormonal Regulation and Hypertension、Birth, Development, and Health

Background Dopamine D 5 receptor (D 5 R) plays an important role in the maintenance of blood pressure by regulating renal sodium transport. Our previous study found that human D 5 R mutant F173L transgenic ( hD 5 R F173L ‐TG) mice are hypertensive. In the present study, we aimed to investigate the mechanisms causing this renal D 5 R dysfunction in hD 5 R F173L ‐TG mice. Methods and Results Compared with wild‐type D 5 R‐TG ( hD 5 R WT ‐TG) mice, hD 5 R F173L ‐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 hD 5 R F173L ‐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 hD 5 R F173L , but is normalized by treatment with exogenous recombinant human Trx1 protein. Regulation of Trx1 by D 5 R occurs by the phospholipase C/ protein kinase C (PKC) pathway because upregulation of Trx1 expression by D 5 R does not occur in renal proximal tubule cells from D 1 R knockout mice in the presence of a phospholipase C or PKC inhibitor. Fenoldopam, a D 1 R and D 5 R agonist, stimulates PKC activity in primary renal proximal tubule cells of hD5R WT ‐ TG mice, but not in those of hD 5 R F173L ‐TG mice. Hyperphosphorylation of hD 5 R F173L and its dissociation from Gαs and Gαq are associated with impairment of D 5...