Role of UCP2 on mitochondrial dysfunction in the renal oxidative stress‐mediated hypertension associated with DJ‐1 depletion
Authors: De Miguel Carmen , Hamrick William C , Jagarlamudi Sudha , Assico Laureano , Jose Pedro A , Cuevas Santiago 
Published: November 2023

DJ‐1 and uncoupling protein 2 (UCP2) exert a protective role against mitochondrial oxidative stress. DJ‐1−/− mice, relative to wild‐type (WT) littermates, have increased systolic BP (30±3%). This study determined the mechanisms involved in the oxidative stress‐mediated hypertension due to DJ‐1 germline deletion. There were no differences in the sodium excretion and renal renin expression between DJ‐1−/− and WT mice (n=5). H&E and picro sirius red staining did not show any abnormalities in renal morphology, including fibrosis in the kidneys of DJ‐1−/− mice. Renal NADPH oxidase activity (n=12) and serum creatinine levels were also not different between the two genotypes. However, the renal expression of nitro‐tyrosine was increased in DJ‐1−/− mice relative to their WT littermates (+176.8±31% vs WT mice, n=5). Tempol, a membrane‐permeable radical scavenger, normalized the BP (tempol: 118±2% vs 100±1% vs WT, n=4) and renal malondialdehyde production (tempol:160±23% vs 109±15% vs WT, n=4) in DJ‐1−/− mice, but had no effect in WT. Tempol‐treated DJ‐1−/− mice had higher serum nitrite/nitrate levels than placebo‐treated DJ‐1−/− mice (172±30% vs WT, n=4) suggesting a role of nitrate radicals on the high blood pressure of this model. Excretion of the renal damage marker KIM‐1 which was increased in DJ‐1−/− mice versus WT (148±22% vs WT, n=4) was decreased by tempol (−58±3% vs WT, n=4). By contrast, heat shock protein mtHSP60, but not mtHSP40, was increased in DJ‐1−/− mice (2.9±0.1 fold changes of WT, n=4), indicating mitochondrial stress. However, there were no changes in the renal mRNA expression of mitophagy markers Nix/BNIP3L, BNIP3, and PINK, mitochondrial fusion markers FIS1, MFN1 and MFN2 and mitochondrial biogenesis markers PPRC1, NRF‐1 and PGC1, indicating that, despite the high mitochondrial ROS production, mitochondrial function was not altered. Renal expression of UCP2 was elevated in DJ‐1−/− mice (4.1±1.1 fold change of WT, n=4), and was partially normalized by tempol (1.8±0.2 fold change of WT, n=4) indicating UCP2 may have a protective role on mitochondrial function in this model. UCP2 expression was silenced in mouse kidney via renal sub‐capsular infusion of siRNA UCP2 in WT and DJ‐1−/− mice (WT: 63%±7 vs control: DJ‐1−/− :60%±6 vs control; n=4). Interestingly, mRNA expression of mitophagy makers BNIP3 (−0.65±6 fold change of WT) and PINK1 (1.55±0.3 fold change of WT of WT), mitochondrial fusion and fission makers FIS1 (−0.29±0.03 fold‐change of WT) NFN2 (1.42±0.06 fold‐change of WT) and mitochondrial biosynthesis maker PPRC1 (1.71±0.07‐fold change of WT; n=4) had significant changes after the UCP2 transfection in DJ‐1−/− mice but not in WT. However no differences were found on NRF1 expression. In conclusion, deletion of DJ‐1 leads to oxidative stress‐induced hypertension mediated by the down‐regulation of NO function, and UCP2 seems to have a protective role against development of mitochondrial dysfunction in mitochondrial oxidative stress, conditions which may have important implications in the prevention of renal disease.