METTL10 attenuates adriamycin-induced podocyte injury by targeting cell dedifferentiation.

Chronic kidney disease (CKD) is a worldwide public health problem. Podocyte damage is a hallmark of glomerular diseases including focal segmental glomerulosclerosis (FSGS) and one of the leading causes of CKD. Lysine methylation is a crucial post-translational modification. Beyond epidemic regulation, various lysine methyltransferases have been recently reported to participate in disease progression, including cancers and kidney diseases. Among them, Methyltransferase-like 10 (METTL10), is recognized as a gene associated with estimated glomerular filtration rate (eGFR) and CKD risk. However, its role in podocyte damage remains unclear. We identified the differentially expressed genes(DEGs)in podocyte injury by bioinformatics analysis. Patients diagnosed as idiopathic FSGS by renal biopsy were enrolled. Mouse model was established by Adriamycin(ADR) and urinary albumin/ creatinine ratio(UACR) was detected. Murine podocyte cell line was stimulated with ADR. We determined METTL10 was one of the significantly downregulated genes in damaged podocytes, confirmed the decreased glomerular expression of METTL10 in patients with idiopathic FSGS and in mice with ADR-induced nephrosis, respectively. Moreover, we found a negative correlation between glomerular METTL10 levels and UACR in mice. METTL10 was reduced in ADR-treated podocytes, accompanied by podocyte dedifferentiation (loss of synaptopodin, podocin, nephrin, WT-1) and acquisition of mesenchymal cell markers (snail, desmin, pax2). Knockdown of METTL10 promoted their dedifferentiation. METTL10 regulates podocyte dedifferentiation under damaging stimuli and protects podocytes.