Department of Nephrology, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi, P.R. China.
Department of Hematology, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi, P.R. China.
Ren Fail. 2024 Dec;46(2):2415517. doi: 10.1080/0886022X.2024.2415517. Epub 2024 Oct 16.
This study explored the effect and mechanism of MAFF and HDAC6 on renal fibrosis and inflammation in lupus nephritis (LN).
IL-33 treated renal epithelial cells and MRL/lpr mice were respectively used for and experiments. The expressions of HDAC6, MAFF, and KLF5 were measured in cells and renal tissues. Before and after cell transfection, the morphological changes in renal tissues were observed using Hematoxylin and eosin (H&E) and Masson staining. The proteinuria, serum creatinine (SCr), blood urea nitrogen (BUN), and double-stranded DNA (dsDNA) levels were detected by biochemical analysis. The expressions of fibrosis and inflammation related proteins (including α-SMA, Vimentin, IL-1β, IL-6, and TNF-α), p65, and iNOS were also detected. The relationship among MAFF, HDAC6, and KLF5 was determined by chromatin immunoprecipitation and dual luciferase reporter gene assay.
Renal tissues and cell models had elevated expressions of HDAC6 and KLF5, and decreased MAFF expression. HDAC6 suppression or MAFF overexpression led to suppression of proteinuria, SCr, BUN, and dsDNA levels, as well as attenuation of inflammatory infiltration and collagen deposition. HDAC6 can suppress MAFF expression deacetylation to abolish its suppression of KLF5 expression, thus increasing KLF5 expression. and experiments showed the suppressive effect of HDAC6 suppression on renal fibrosis and inflammation can be abolished by KLF5 overexpression.
HDAC6 suppresses MAFF expression deacetylation to elevate KLF5 expression, which consequently enhances fibrosis and inflammatory response in LN.
本研究旨在探讨 MAFF 和 HDAC6 对狼疮肾炎（LN）肾纤维化和炎症的作用及机制。
分别采用 IL-33 处理的肾上皮细胞和 MRL/lpr 小鼠进行 和 实验。检测细胞和肾组织中 HDAC6、MAFF 和 KLF5 的表达。细胞转染前后，采用苏木精和伊红（H&E）及 Masson 染色观察肾组织形态学变化。采用生化分析检测蛋白尿、血清肌酐（SCr）、血尿素氮（BUN）和双链 DNA（dsDNA）水平。检测纤维化和炎症相关蛋白（包括 α-SMA、波形蛋白、IL-1β、IL-6 和 TNF-α）、p65 和 iNOS 的表达。通过染色质免疫沉淀和双荧光素酶报告基因检测确定 MAFF、HDAC6 和 KLF5 之间的关系。
肾组织和细胞模型中 HDAC6 和 KLF5 的表达升高，MAFF 表达降低。抑制 HDAC6 或过表达 MAFF 可抑制蛋白尿、SCr、BUN 和 dsDNA 水平的升高，减轻炎症浸润和胶原沉积。HDAC6 可通过去乙酰化抑制 MAFF 表达，从而消除其对 KLF5 表达的抑制作用，增加 KLF5 表达。 和 实验表明，过表达 KLF5 可消除抑制 HDAC6 对 LN 肾纤维化和炎症的抑制作用。
HDAC6 通过去乙酰化抑制 MAFF 表达，从而上调 KLF5 表达，进而增强 LN 中的纤维化和炎症反应。
