ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy

• Published in: Life sciences (1973) Vol. 264; p. 118686
• Main Authors: Liang, Qiuer, Liu, Tianhao, Guo, Tingting, Tao, Wencong, Chen, Xudong, Chen, Weihao, Chen, Liguo, Xiao, Ya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2021; Elsevier BV
• Subjects: Activated transcription factor-4; Activating transcription factor 4; Activating Transcription Factor 4 - biosynthesis; Activating Transcription Factor 4 - genetics; Albumins; Animals; Autophagy; Autophagy - physiology; Collagen; Creatinine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; End-stage renal disease; Extracellular matrix; Fibrosis; Fluorescence; Fluorescence microscopy; Glucose; Histology; Immunofluorescence; Kidney diseases; Kidneys; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopic analysis; Nephritis, Interstitial - genetics; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephropathy; Phagocytosis; Phagosomes; Renal tubulointerstitial fibrosis; Streptozocin; Urea; Diabetic nephropathy; Renal tubulointerstitial fibrosis; Activated transcription factor-4; Autophagy
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.118686

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.