Endophilin A2 protects against renal fibrosis by targeting TGF-β/Smad signaling.

Xiaoyi Mai, Jinyan Shang, Qiuyuan Chen, Shijie Gu, Yu Hong, Jiaguo Zhou, Minzhou Zhang

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2022 Nov

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Renal fibrosis underlies all forms of end-stage kidney disease. Endophilin A2 (EndoA2) plays a role in nephrotic syndrome; however, its effect on renal fibrosis remains unknown. Here, we demonstrate that EndoA2 protects against kidney interstitial fibrosis via the transforming growth factor-β (TGF-β)/Smad signaling pathway. Mouse kidneys with fibrosis or kidney biopsy specimens from patients with fibrotic nephropathy had lower levels of EndoA2 protein expression than that in kidneys without fibrosis. In vivo overexpression of EndoA2 with the endophilin A2 transgene (EndoA2Tg ) notably prevented renal fibrosis, decreased the protein expression of profibrotic molecules, suppressed tubular injury, and reduced apoptotic tubular cells in the obstructed kidney cortex of mice with unilateral ureteral obstruction (UUO). In vivo and in vitro overexpression of EndoA2 markedly inhibited UUO- or TGF-β1-induced phosphorylation of Smad2/3 and tubular epithelial cells dedifferentiation. Furthermore, EndoA2 was co-immunoprecipitated with the type II TGF-β receptor (TβRII), thus inhibiting the binding of the type I TGF-β receptor (TβRI) to TβRII. These findings indicate that EndoA2 mitigates renal fibrosis, at least partially, via modulating the TGF-β/Smad signaling. Targeting EndoA2 may be a new potential therapeutic strategy for treatment of renal fibrosis. © 2022 Federation of American Societies for Experimental Biology.

Citation

Xiaoyi Mai, Jinyan Shang, Qiuyuan Chen, Shijie Gu, Yu Hong, Jiaguo Zhou, Minzhou Zhang. Endophilin A2 protects against renal fibrosis by targeting TGF-β/Smad signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 Nov;36(11):e22603