Selective Inhibition of Histone Deacetylase Class IIa With MC1568 Ameliorates Podocyte Injury

Xu He; Tao Sun; Pei Zhang; Zhengkun Xia; Chunlin Gao; Hongqi Ren; Daxi Ji

doi:10.3389/fmed.2022.848938

Selective Inhibition of Histone Deacetylase Class IIa With MC1568 Ameliorates Podocyte Injury

Front Med (Lausanne). 2022 Apr 14:9:848938. doi: 10.3389/fmed.2022.848938. eCollection 2022.

Authors

Xu He¹, Tao Sun², Pei Zhang², Zhengkun Xia², Chunlin Gao², Hongqi Ren³, Daxi Ji^{1

4}

Affiliations

¹ Department of Pediatrics, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
² Department of Pediatrics, Jinling Hospital, Nanjing, China.
³ Department of Nephrology, Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, China.
⁴ Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Histone deacetylases (HDACs) inhibitors are promising therapeutic agents against proteinuric kidney diseases, here, we investigated the effect of MC1568, a selective inhibitor of HDAC class IIa, on the development and progression of nephrotic syndrome in a murine model induced by Adriamycin (ADR). In kidney tissues of FSGS patients, all four members of HDAC IIa were significantly upregulated in podocytes. In ADR-treated cultured human podocyte, expression of HDAC IIa were induced, meanwhile inhibition of HDAC IIa with MC1568 restored cytoskeleton structure and suppressed expression of desmin and α-SMA. In mice, administration of MC1568 at 14 days after ADR ameliorated proteinuria and podocyte injury, also decreased expression of Fibronectin and α-SMA. Mechanistically, MC1568 inhibited ADR induced β-catenin activation in vitro and in vivo. Together, these finding demonstrate that HDAC IIa inhibition ameliorates podocyte injury and proteinuria, which provide a possibility that MC1568 may be used in nephrotic syndrome.

Keywords: HDAC; nephrotic syndrome; podocyte injury; proteinuria; β-catenin.