Uncoupling Protein 2 Increases Blood Pressure in DJ‐1 Knockout Mice

BACKGROUND: The redox‐sensitive chaperone DJ‐1 and uncoupling protein 2 are protective against mitochondrial oxidative stress. We previously reported that renal‐selective depletion and germline deletion of DJ‐1 increases blood pressure in mice. This study aimed to determine the mechanisms involved in the oxidative stress–mediated hypertension in DJ‐1 (−/−) mice. METHODS AND RESULTS: There were no differences in sodium excretion, renal renin expression, renal NADPH oxidase activity, and serum creatinine levels between DJ‐1 (−/−) and wild‐type mice. Renal expression of nitro‐tyrosine, malondialdehyde, and urinary kidney injury marker‐1 were increased in DJ‐1 (−/−) mice relative to wild‐type littermates. mRNA expression of mitochondrial heat shock protein 60 was also elevated in kidneys from DJ‐1 (−/−) mice, indicating the presence of oxidative stress. Tempol‐treated DJ‐1 (−/−) mice presented higher serum nitrite/nitrate levels than vehicle‐treated DJ‐1 (−/−) mice, suggesting a role of the NO system in the high blood pressure of this model. Tempol treatment normalized renal kidney injury marker‐1 and malondialdehyde expression as well as blood pressure in DJ‐1 (−/−) mice, but had no effect in wild‐type mice. The renal Ucp2 mRNA expression was increased in DJ‐1 (−/−) mice versus wild‐type and was also normalized by tempol. The renal‐selective silencing of Ucp2 led to normalization of blood pressure and serum nitrite/nitrate ratio in DJ‐1 (−/−) mice. CONCLUSIONS: The deletion of DJ‐1 leads to oxidative stress–induced hypertension associated with downregulation of NO function, and overexpression of Ucp2 in the kidney increases blood pressure in DJ‐1 (−/−) mice. To our knowledge, this is the first report providing evidence of the role of uncoupling protein 2 in blood pressure regulation.