Histone lysine-specific demethylase 1 induced renal fibrosis via decreasing sirtuin 3 expression and activating TGF-β1/Smad3 pathway in diabetic nephropathy

Diabetology & Metabolic Syndrome

Jin Zhong¹  Lei Yu²  Lina Dong² 

[1] Department of Nephrology, Chongqing Hospital of Traditional Chinese Medicine, No. 6 Panxiqizhi Road, Jiangbei District, Chongqing, China;Department of Nephrology, Inner Mongolia People’s Hospital, 010010, Hohhot, Inner Mongolia Autonomous Region, China;

关键词: LSD1;    Renal fibrosis;    Diabetic nephropathy;    TGF-β1/Smad3 pathway;    SIRT3;   

DOI  :  10.1186/s13098-021-00771-z

来源: Springer

【 摘 要 】

ObjectiveDiabetic nephropathy (DN) is the leading cause of end-stage renal disease. Histone lysine-specific demethylase 1 (LSD1) is a flavin-containing amino oxidase that can repress or activate transcription. The aim of this study is to explore the mechanism of LSD1 aggravating DN-induced renal fibrosis.MethodsThe STZ-induced DN rat model was established for in vivo study. The rats were divided into four groups: Sham, STZ, STZ + Ad-shNC and Ad-shLSD1. The Hematoxylin–eosin (HE) staining was used to evaluate the renal injury. The Immunofluorescence assay was used to determine the LSD1, Fibronectin and α-SMA expression. The related protein expression was detected by western blot.ResultsKnockdown of LSD1 alleviated STZ-induced renal injury. Moreover, knockdown of LSD1 decreased the expression of serum biochemical markers, containing urine output (24 h), urinary protein (24 h), serum creatinine, BUN and UACR. Furthermore, we proved that knockdown of LSD1 alleviated renal fibrosis in STZ-induced DN rats. In vitro, knockdown of LSD1 suppressed NRK-49F cells activation and overexpression of LSD1 induced renal fibrosis. In addition, knockdown of LSD1 could deactivate TGF-β1/Smad3 pathway and promote sirtuin 3 (SIRT3) expression in vivo and in vitro. The rescue experiments confirmed that LSD1 induced renal fibrosis via decreasing SIRT3 expression and activating TGF-β1/Smad3 pathway.ConclusionLSD1 deficiency leads to alleviate STZ-induced renal injury and overexpression of LSD1 induces renal fibrosis via decreasing SIRT3 expression and activating TGF-β1/Smad3 pathway, which provides a reasonable strategy for developing novel drugs targeting LDS1 to block renal fibrosis.

【 授权许可】

CC BY