He Xu, Sun Tao, Zhang Pei, Xia Zhengkun, Gao Chunlin, Ren Hongqi, Ji Daxi
Department of Pediatrics, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Department of Pediatrics, Jinling Hospital, Nanjing, China.
Front Med (Lausanne). 2022 Apr 14;9:848938. doi: 10.3389/fmed.2022.848938. eCollection 2022.
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 and . 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.
组蛋白去乙酰化酶（HDACs）抑制剂是治疗蛋白尿性肾脏疾病的有前景的治疗药物。在此，我们研究了IIa类HDAC的选择性抑制剂MC1568对阿霉素（ADR）诱导的小鼠肾病综合征发展和进展的影响。在局灶节段性肾小球硬化（FSGS）患者的肾组织中，IIa类HDAC的所有四个成员在足细胞中均显著上调。在ADR处理的培养的人足细胞中，IIa类HDAC的表达被诱导，同时用MC1568抑制IIa类HDAC可恢复细胞骨架结构并抑制结蛋白和α-平滑肌肌动蛋白（α-SMA）的表达。在小鼠中，ADR后14天给予MC1568可改善蛋白尿和足细胞损伤，也可降低纤连蛋白和α-SMA的表达。机制上，MC1568抑制ADR诱导的β-连环蛋白激活。总之，这些发现表明抑制IIa类HDAC可改善足细胞损伤和蛋白尿，这为MC1568可用于肾病综合征提供了可能性。
