WTAP Deficiency Promotes Podocyte PANoptosis and FSGS via SPP1 Signaling.

Abstract

Focal segmental glomerulosclerosis (FSGS) is a major cause of primary glomerular disease, characterized by progressive podocyte injury and loss. This study aimed to identify the RNA methylation regulator WTAP (Wilms' tumor 1-associated protein) as a novel pathogenic factor in FSGS. WTAP expression in podocytes was detected in kidney biopsies from patients with FSGS and in an adriamycin-induced FSGS mouse model. Two podocyte-specific Wtap-deficient mouse models were generated using the Cre-loxP system: a constitutive knockout (cKO) model and a tamoxifen-inducible knockout model. Loss- and gain-of-function strategies were used to investigate the functional role of WTAP in podocytes both in vivo and in vitro. WTAP expression was significantly decreased in podocytes from patients with FSGS and in the adriamycin-induced FSGS mouse model. Both cKO and tamoxifen-inducible knockout mice developed progressive glomerulosclerosis with characteristic features of FSGS. WTAP overexpression in podocytes attenuated podocyte injury both in vivo and in vitro. cKO mice exhibited alterations in the proportions of various renal cell types, including both renal intrinsic and inflammatory cells. Mechanistically, WTAP regulates SPP1 m⁶A methylation, thereby modulating its stability and expression. Notably, SPP1-mediated signaling emerged as a central hub coordinating pathological cell-cell interactions in cKO mouse kidneys, and neutralization of SPP1 significantly ameliorated renal injury in both cKO and adriamycin-induced FSGS mice. We successfully constructed 2 FSGS mouse models that are suitable for investigating the pathogenic mechanisms and therapeutic targets of FSGS. Our findings demonstrate that the WTAP/SPP1 (secreted phosphoprotein 1) signaling pathway contributes to the renal pathological changes in FSGS, suggesting that targeting this pathway may represent a promising therapeutic strategy.