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Background and Aims Diabetic nephropathy (DN) can cause end-stage renal disease. During the progression of DN, hyperglycemia accelerates the senescence of renal tubular epithelial cells (RTECs), leading to the tubulointerstitial inflammation and fibrosis. E3-ubiquitin ligase Parkin can regulate several pathophysiological processes. This study explored the role and mechanisms of Parkin in the progression of diabetic nephropathy (DN). Method 149 cases of patients with DN diagnosed by renal biopsy were recruited in our study. 32 normal kidney samples were obtained from renal carcinoma as control. Renal Parkin expression was detected by immunohistochemistry. The correlation between Parkin expression and renal pathological injury scores, renal function injury parameters were analyzed. In vivo, we generated Parkin overexpressed streptozotocin-induced DN mice using ultrasound- mediated adenovirus transfection. In vitro, knockdown and overexpression experiments were performed by parkin siRNA or Parkin overexpressed adenovirus in high glucose (HG) stimulated mouse primary RTEC. Moreover, we used co-immunoprecipitation and pull down experiments to evaluate the interaction of GATA4 with parkin. Results We found that Parkin expression gradually decreased and was inversely associated with IL-6, TGF-β1 and GATA4 expression in the kidney during the progression of DN. Parkin over-expression (OE) reduced inflammation, fibrosis, premature senescence of RTECs and improved renal function while Parkin knockout (KO) had opposite effects in DN mice. Parkin-OE decreased GATA4 protein, but not its mRNA transcripts in the kidney of DN mice and high glucose (HG)-treated RTECs. Immunoprecipitation indicated that Parkin directly interacted with GATA4 in DN kidney. Parkin-OE enhanced GATA4 ubiquitination. Furthermore, Parkin-KO up-regulated growth arrest specific gene 1 (GAS1) expression in renal tubular tissues of DN mice and GATA4-OE enhanced the HG-up-regulated GAS1 expression in RTECs. Conversely, GAS1-OE mitigated the effect of Parkin-OE on HG-induced P21, IL-6 and TGF-β1 expression in RTECs. These results indicate that Parkin inhibits the progression of DN by promoting GATA4 ubiquitination and downregulating the GATA4/GAS1 signaling to inhibit premature senescence, inflammation and fibrosis in DN mice. Thus, these findings uncover new mechanisms underlying the action of Parkin during the process of DN. Conclusion Parkin inhibited the progression of DN by promoting GATA4 ubiquitination and downregulating the GATA4/GAS1 signaling to inhibit premature senescence, inflammation and fibrosis. Our findings uncover a novel endogenous protective mechanism by which Parkin regulates the senescence of RTECs, inflammation and fibrosis during the pathogenesis of DN.

P0969PARKIN INHIBITS THE PROGRESSION OF DIABETIC NEPHROPATHY BY PROMOTING GATA4 DEGRADATION TO REDUCE THE SENESCENCE OF RENAL TUBULAR CELLS