FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy

• DOI: 10.1016/j.yexcr.2021.112863
• Publication Date: 2021-10-07T07:17:42Z
• Authors: Xiaohong Xu; Liexiang Zhang; Fei Hua; Ce Zhang; Chi Zhang; Xia Mi; Nan Qin; Junsheng Wang; Aimin Zhu; Zihan Qin; Feihong Zhou
• Keywords: 0303 health sciences; Inflammasomes; Podocytes; Forkhead Box Protein M1; NF-kappa B; Acute Kidney Injury; Kidney; 3. Good health; Mitochondrial Proteins; Mice; 03 medical and health sciences; Gene Expression Regulation; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Animals; Humans; Sirtuins; Diabetic Nephropathies; Signal Transduction

Forkhead box M1 (FOXM1) has been reported to play a protective role against acute kidney injury by driving tubular regeneration. This study aims to probe the function of FOXM1 in diabetic nephropathy (DN) and the molecules involved. FOXM1 was poorly expressed in DN-diseased kidney tissues. A murine model of DN was established, and podocytes cells (MPC5) were treated with high-glucose (HG) for in vitro studies. FOXM1 overexpression improved kidney function and reduced pathological changes in mice, and it increased the expression of the podocyte marker Nephrin in kidney tissues. In vitro, FOXM1 increased viability and reduced pyroptosis of the HG-treated MPC5 cells, and it elevated the expression of the podocyte marker Nephrin whereas reduced the expression of pyroptosis-related NLRP3 inflammasome and cleaved caspase 1. FOXM1 bound to the promoter of sirtuin 4 (SIRT4) to induce transcriptional activation. Downregulation of SIRT4 blocked the protective roles of FOXM1 both in vivo and in vitro. Phosphorylation of nuclear factor-kappa B (NF-κB) in HG-treated cells was suppressed by FOXM1 but restored after SIRT4 inhibition. In conclusion, this study suggested that FOXM1 transcriptionally activates SIRT4 and inhibits NF-κB signaling and the NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in DN.