Abstract
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.
Highlights
Diabetic nephropathy (DN) is one of the main microvascular complications of diabetes, and it can cause end-stage renal disease, which is characterized by renal hyperplasia, basement membrane thickening andDong et al Diabetology & Metabolic Syndrome (2022) 14:2 identify new pathologic mediators and therapeutic targets to prevent the progression of DN.Epigenetic modifications mainly include genomic DNA methylation and histone modification
The IF staining indicated that Ad-shLSD1 markedly reduced the lysine-specific demethylase 1 (LSD1) expression in Knockdown of LSD1 decreases the expression of serum biochemical markers After injected with STZ, the blood glucose was ≥ 16.7 mmol/L, the urine output volume was greater than 50% of the rats Sham rats, the urinary protein was > 30 mg/24 h, indicating that the STZ-induced DN rat model was successfully established
Knockdown of LSD1 significantly reduced STZ-induced blood glucose, urine output (24 h), urinary protein (24 h), serum creatinine, blood urea nitrogen (BUN) and urinary albumin-to-creatinine ratio (UACR) (Fig. 2). These results concluded that knockdown of LSD1 decreased the expression of serum biochemical markers in STZ-induced DN rats
Summary
Epigenetic modifications mainly include genomic DNA methylation and histone modification. Histone methylation is a method of altering transcription by providing docking sites for chromatin modification instead of the charge of lysine [5]. Histone lysine-specific demethylase 1 (LSD1), known as KDM1A, is a flavin-containing amino oxidase that removes methyl groups from mono- and demethylated Lys and Lys of histone (H3K4Me1/2 and H3K9Me1/2) [7, 8]. In hepatitis B virus-associated glomerulonephritis, LSD1 promotes renal inflammation by mediating TLR4 signaling pathway, and LSD1 positive is positively correlated with renal interstitial fibrosis [15]. A recent study has reported that LSD1 activation contributes to pulmonary myofibroblast differentiation and fibrosis by targeting TGF-β1/Smad signaling [17]. The mechanism of LSD1 in DN-induced renal fibrosis has not been reported
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