ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy

摘要

Aim: 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. @@@ Main method: 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. @@@ Key findings: 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. @@@ Significance: 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.

关键词