ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy.

Qiuer Liang, Tianhao Liu, Tingting Guo, Wencong Tao, Xudong Chen, Weihao Chen, Liguo Chen, Ya Xiao

Life sciences 2021 Jan 01

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Diabetic nephropathy (DN) is the dominant cause of end-stage renal disease which is characterized by extracellular matrix accumulation. The purpose of this study was to investigate the role of activating transcription factor 4 (ATF4) in regulating renal fibrosis and autophagy in DN. Streptozotocin (STZ) was administered to heterozygous ATF4 knockout (KO) and wild-type (WT) mice via an intraperitoneal injection to induce DN. NRK-52E cells were cultured in high glucose to mimic diabetic pathological. qRT-PCR, western blot, immunofluorescence, histology and electron microscopic analysis were performed. The autophagy flux was observed by tandem mRFP-GFP-LC3 fluorescence microscopy. DN mice experienced severe renal injury and fibrosis and showed increased expression of ATF4 and inhibition of autophagy in kidney tissues. We found that STZ-induced ATF4 KO mice showed significant improvement in urinary albumin, serum creatinine and blood urea nitrogen and the pathological changes of renal tubulointerstitial fibrosis compared with STZ-induced WT mice. Furthermore, inhibition of ATF4 could restore autophagy in DN mice. Similar results were shown in vitro. Overexpression of ATF4 in NRK-52E cells cultured in high glucose condition suppressed autophagy and upregulated Collagen type 4 (Col-IV) expression, while inhibition of ATF4 could increase the number of the autophagosomes, improve autophagic flux and decrease Col-IV level. Our study provided the evidence of a crucial role for ATF4 in inhibiting autophagy against diabetic kidney damage. Suppression of ATF4 may be an effective therapy in restraining renal tubulointerstitial fibrosis in DN. Copyright © 2020. Published by Elsevier Inc.

Citation

Qiuer Liang, Tianhao Liu, Tingting Guo, Wencong Tao, Xudong Chen, Weihao Chen, Liguo Chen, Ya Xiao. ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy. Life sciences. 2021 Jan 01;264:118686