PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling

Abstract

Impaired glucose uptake regulated by suppressed insulin receptor signaling is a key driving force of podocytopathies. The identification of potential therapeutic targets that mediate podocyte insulin receptor signaling holds significant clinical importance. Here, we observed a substantial reduction in PR domain-containing 16 (PRDM16) expression within damaged podocytes in both humans and mice. Podocyte-specific Prdm16 deletion aggravated podocyte injury, albuminuria, and glomerulosclerosis in diabetic nephropathy (DN) mice. Conversely, exogenous PRDM16 delivered by lentivirus mitigated these pathological changes in DN mice and adriamycin (ADR) nephropathy mice. Furthermore, we demonstrated that loss of PRDM16 blocked glucose uptake of podocytes by inhibiting insulin receptor signaling. Mechanistically, PRDM16 deficiency downregulated the transcription of NEDD4L, subsequently enhancing the stability of IKKβ protein. The accumulation of IKKβ caused by the loss of PRDM16 led to the phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1), thereby promoting IRS-1 degradation. Exogenous NEDD4L mitigated podocyte injury induced by PRDM16 knockdown in vitro and attenuated ADR nephropathy in vivo. Our study clarified the role and mechanism of PRDM16 in insulin receptor signaling and podocyte injury, providing a potential therapeutic target for podocytopathies.