Methylation in pericytes after acute injury promotes chronic kidney disease

• Published in: The Journal of clinical investigation 2020-09, Vol.130 (9), p.4845-4857
• Main Authors: Chou, Yu-Hsiang, Pan, Szu-Yu, Shao, Yu-Han, Shih, Hong-Mou, Wei, Shi-Yao, Lai, Chun-Fu, Chiang, Wen-Chih, Schrimpf, Claudia, Yang, Kai-Chien, Lai, Liang-Chuan, Chen, Yung-Ming, Chu, Tzong-Shinn, Lin, Shuei-Liong
• Format: Article
• Language: English
• Subjects: Ablation; Actin; Acute Kidney Injury - complications; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Adenine; Animals; Apoptosis; Azacytidine; Biomedical research; Bone morphogenetic proteins; Cell cycle; Chronic kidney failure; Creatinine; Demethylation; DNA Methylation; DNA microarrays; Epigenetic inheritance; Gene expression; Growth factors; Ischemia; Kidney diseases; Methylation; Mice; Mice, Transgenic; Microvasculature; Oligonucleotide Array Sequence Analysis; Pericytes; Pericytes - metabolism; Pericytes - pathology; Principal components analysis; Proteins; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Reperfusion; Reperfusion Injury - complications; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Smooth muscle
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI135773

The origin and fate of renal myofibroblasts is not clear after acute kidney injury (AKI). Here, we demonstrate that myofibroblasts were activated from quiescent pericytes (qPericytes) and the cell numbers increased after ischemia/reperfusion injury-induced AKI (IRI-AKI). Myofibroblasts underwent apoptosis during renal recovery but one-fifth of them survived in the recovered kidneys on day 28 after IRI-AKI and their cell numbers increased again after day 56. Microarray data showed the distinctive gene expression patterns of qPericytes, activated pericytes (aPericytes, myofibroblasts), and inactivated pericytes (iPericytes) isolated from kidneys before, on day 7, and on day 28 after IRI-AKI. Hypermethylation of the Acta2 repressor Ybx2 during IRI-AKI resulted in epigenetic modification of iPericytes to promote the transition to chronic kidney disease (CKD) and aggravated fibrogenesis induced by a second AKI induced by adenine. Mechanistically, transforming growth factor-β1 decreased the binding of YBX2 to the promoter of Acta2 and induced Ybx2 hypermethylation, thereby increasing α-smooth muscle actin expression in aPericytes. Demethylation by 5-azacytidine recovered the microvascular stabilizing function of aPericytes, reversed the profibrotic property of iPericytes, prevented AKI-CKD transition, and attenuated fibrogenesis induced by a second adenine-AKI. In conclusion, intervention to erase hypermethylation of pericytes after AKI provides a strategy to stop the transition to CKD.