Glycine decarboxylase advances IgA nephropathy by boosting mesangial cell proliferation through the pyrimidine pathway

Abstract The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC’s regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.