Mitogen-activating protein kinase kinase kinase kinase-3, inhibited by Astragaloside IV through H3 lysine 4 monomethylation, promotes the progression of diabetic nephropathy by inducing apoptosis

Abstract

Astragaloside IV (AS-IV) is a bioactive saponin extracted from the Astragalus root and has been reported to exert a protective effect on diabetic nephropathy (DN). However, the underlying mechanism remains unclear. Herein, we found that AS-IV treatment alleviated DN symptoms in DN mice accompanied by reduced metabolic parameters (body weight, urine microalbumin and creatinine, creatinine clearance, and serum urea nitrogen and creatinine), pathological changes, and apoptosis. Epigenetic histone modifications are closely related to diabetes and its complications, including H3 lysine 4 monomethylation (H3K4me1, a promoter of gene transcription). A ChIP-seq assay was conducted to identify the genes regulated by H3K4me1 in DN mice after AS-IV treatment and followed by a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The results showed that there were 16 common genes targeted by H3K4me1 in normal and AS-IV-treated DN mice, 1148 genes were targeted by H3K4me1 only in DN mice. From the 1148 genes, we screened mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) for the verification of gene expression and functional study. The results showed that MAP4K3 was significantly increased in DN mice and high glucose (HG)-treated NRK-52E cells, which was reversed by AS-IV. MAP4K3 silencing reduced the apoptosis of NRK-52E cells under HG condition, as evidenced by decreased cleaved caspase 3 and Bax (pro-apoptotic factors), and increased Bcl-2 and Bcl-xl (anti-apoptotic factors). Collectively, AS-IV may downregulate MAP4K3 expression by regulating H3K4me1 binding and further reducing apoptosis, which may be one of the potential mechanisms that AS-IV plays a protective effect on DN.

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

“…Indeed, histone acetylation and methylation are implicated in the propagation of inflammation, oxidative stress and fibrosis in the kidney. Even though the exact mechanism(s) through which impaired epigenetic landscape contributes to DKD is still unclear, it appears that an altered enhancer landscape plays an important role [ 112 , 113 , 114 ]. It remains to be established whether targeting this pathway might prevent the development or delay the progression of DKD.…”

Study of molecular mechanisms underlying the medicinal plant Tripterygium wilfordii-derived compound celastrol in treating diabetic nephropathy based on network pharmacology and molecular docking

“…An increasing number of studies demonstrates that cell apoptosis is one of the major mechanisms in the development and progression of DN. Elevated apoptosis has been found in the kidneys of DN patients and suppression of the cell apoptosis in DN mice could mitigate DN symptoms (Fan et al, 2022). It was previously revealed that celastrol pre-treatment reversed HG-induced cell apoptosis to ameliorate the pathological injury of DN (Zhan et al, 2018).…”

Saponin monomers: Potential candidates for the treatment of type 2 diabetes mellitus and its complications

“…He et al, 2023), attenuating podocyte apoptosis (Lei, Zhang, Li, et al, 2018; Xing et al, 2021; Zhang et al, 2023), alleviating renal tubular epithelial–mesenchymal transition (EMT) (X. Chen, Yang, et al, 2019; Hu et al, 2022; Y. N. Wang, Zhao, et al, 2020), and inhibiting mitogen‐activating protein kinase kinase kinase kinase‐3 (MAP4K3) (Y. Fan et al, 2022) and renal tubular epithelial cell apoptosis (Ju et al, 2019). AS‐IV administration significantly reduced urinary albumin excretion and urinary N‐acetyl‐β‐ d ‐glucosaminidase and ameliorated the renal pathologic injury in db/db mice by reducing renal dynamin‐related protein, mitochondrial fission protein 1, and mitochondrial fission factor expression and by downregulating PINK1/Parkin‐mediated mitophagy (X. Liu, Wang, et al, 2017).…”