DJ‐1 protects against renal mitochondrial oxidative stress and T cell infiltration

Abstract

Protein nucleic acid deglycase (DJ‐1) exerts a protective role against oxidative stress. DJ‐1−/− mice have increased systolic BP (30±3%) relative to wild‐type (WT) littermates. This study aimed to determine the mechanisms involved in the oxidative stress‐mediated hypertension due to DJ‐1 germline deletion. At baseline, no differences were found in sodium excretion, renal expression of renin, NADPH activity or serum creatinine levels between DJ‐1−/− and WT mice (n=5–12). Histological assessment by H&E and Picro Sirius demonstrated no kidney morphological abnormalities associated to DJ‐1 deletion. However, renal expression of nitrotyrosine was elevated in DJ‐1−/− mice (+176.8±31% vs. WT mice, n=5), and urinary excretion of the renal damage marker KIM‐1 was increased in DJ‐1−/− mice (148±22% vs WT, n=4), indicating the presence of oxidative stress and kidney damage in DJ‐1−/− mice. In addition, mRNA expression of mitochondrial heat shock protein mtHSP60, but not mtHSP40, was increased in kidneys from DJ‐1−/− mice (2.9±0.1 fold changes of WT, n=4), evidencing mitochondrial oxidative stress in these mice. Conversely, levels of renal endoplasmic reticulum (ER) stress and renal inflammation were similar between the genotypes, indicating that inflammation was not altered in this animal model, despite the high mitochondrial ROS production. Two week treatment with the membrane‐permeable radical scavenger Tempol normalized BP (vehicle vs. tempol: 118±2 vs. 100±1%, n=4, p<0.05), renal malondialdehyde production (160±23% vs 109±15% vs WT, n=4, p<0.05) and KIM‐1 excretion (‐58±3% vs WT, n=4, p<0.05) in DJ‐1−/− mice, but had no effect in WT mice. Serum nitrite/nitrate levels in DJ‐1−/− mice treated with tempol were significantly elevated compared to vehicle‐treated DJ‐1−/− mice (172±30% DJ‐1−/− tempol vs. vehicle, n=4, p<0.05), suggesting a role of nitric oxide on the high blood pressure observed in this model. To examine if lack of DJ‐1 leads to exaggerated renal inflammation and renal damage after an insult, unilateral ureter obstruction (UUO) was performed in DJ‐1−/− and WT mice. After 2 weeks of UUO, increased cortical T‐cell infiltration was observed in WT mice (225±101%; sham vs. UUO, n=3–4; p<0.05) and it was dramatically exaggerated in the DJ‐1−/− mice (67±14%; WT UUO vs. DJ‐1−/− UUO, n=3; p<0.05). In conclusion, deletion of DJ‐1 leads to mitochondrial oxidative stress‐induced hypertension possibly, due to decreased nitric oxide bioavailability, without altering sodium excretion, renal NAPDH activity, inflammation, morphology or ER stress levels. Our results suggest a protective role of DJ‐1 against renal infiltration of T‐cells in the UUO model of kidney disease and may have important implications in the prevention of renal diseases.Support or Funding InformationFunded by NIH T32 DK007545 to CDM and NIH/NHLBI 5P01 HL074940‐10) and NIH/NHLBI 5P01 HL068686‐11 to PAJThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.