Methylation in pericytes after acute injury promotes chronic kidney disease
Yu-Hsiang Chou, … , Tzong-Shinn Chu, Shuei-Liong Lin
Yu-Hsiang Chou, … , Tzong-Shinn Chu, Shuei-Liong Lin
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(9):4845-4857. https://doi.org/10.1172/JCI135773.
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Methylation in pericytes after acute injury promotes chronic kidney disease

Abstract

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.

Authors

Yu-Hsiang Chou, Szu-Yu Pan, Yu-Han Shao, Hong-Mou Shih, Shi-Yao Wei, Chun-Fu Lai, Wen-Chih Chiang, Claudia Schrimpf, Kai-Chien Yang, Liang-Chuan Lai, Yung-Ming Chen, Tzong-Shinn Chu, Shuei-Liong Lin

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Figure 9

YBX2 repressed the expression of Acta2.

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YBX2 repressed the expression of Acta2. (A) Line chart showing the expre...
(A) Line chart showing the expression of Ybx2 mRNA in the primary kidney pericytes after TGF-β1 exposure and withdrawal at the indicated time points. Data were expressed as the mean ± SEM. n = 3. *P < 0.05 by t test vs. before TGF-β1 withdrawal. (B) Representative images showing the electrophoresis of the PCR products of the Ybx2 gene using MeDIP or input DNA from primary kidney pericytes after TGF-β1 exposure for 24 or 120 hours. Pericytes without TGF-β1 exposure served as the Ctrl. (C) Scheme showing the primer design in the promoter regions of the Acta2 gene. (D) Representative images showing the electrophoresis of PCR products of the promoter of the Acta2 gene using DNA immunoprecipitated by anti-YBX2 antibody (ChIP) or input DNA from the primary kidney pericytes with or without TGF-β1 exposure for 120 hours. ChIP using isotype IgG served as the Ctrl. (E) Representative Western blot analyses for YBX2, αSMA, and β-actin in pericytes with or without lentiviral transduction for YBX2 expression. (F) Dot chart showing the relative expression of YBX2 and αSMA in pericytes with or without lentiviral transduction for YBX2 expression. Horizontal bars represent the mean, error bars represent the SEM. n = 3. **P < 0.01, ***P < 0.001 by 1-way ANOVA with post hoc Tukey’s correction.