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Parkin ubiquitinates GATA4 and attenuates the GATA4/GAS1 signaling and detrimental effects on diabetic nephropathy
Author(s) -
Chen Kehong,
Chen Jia,
Wang Ling,
Yang Jie,
Xiao Fei,
Wang Xianyue,
Yuan Junjie,
Wang Limin,
He Yani
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000053r
Subject(s) - parkin , ubiquitin , downregulation and upregulation , kidney , endocrinology , ubiquitin ligase , diabetic nephropathy , medicine , cancer research , chemistry , biology , gene , biochemistry , disease , parkinson's disease
Renal tubular injury contributes to the progression of diabetic nephropathy ( DN). This study explored the role and mechanisms of E3‐ubiquitin ligase Parkin in the renal tubular injury of DN. 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 renal tubular epithelial cells (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 upregulated growth arrest‐specific gene 1 (GAS1) expression in renal tubular tissues of DN mice and GATA4‐OE enhanced the HG‐upregulated 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.