A functional investigation of the natriuretic peptide receptor 3 (NPR3) in glomerular stability and disease progression

Abstract Podocytes are essential for maintaining the structural and functional integrity of the glomerular filter. While the signaling properties of the natriuretic peptide receptor 3 (NPR3) have long been debated, emerging data suggest a signaling role in podocytes through interactions with slit diaphragm (SD) proteins. However, its functional contribution to glomerular homeostasis remains unclear. To investigate its role, Podocyte-specific Npr3 conditional knockout mice ( Npr3 ΔPOD ) on a C57BL/6 background were exposed to two different models of glomerular injury: DOCA-high salt hypertension and Adriamycin nephropathy. Complementary in vitro phosphoproteomic profiling in CRISPR/Cas9-edited podocyte cell lines were performed to elucidate downstream signaling mediators. DOCA-salt treatment induced significant increases in systolic blood pressure, glomerular injury, and albuminuria in both genotypes without intergenotype differences. Following Adriamycin induction, WT mice developed mild albuminuria, whereas Npr3 ΔPOD mice were significantly protected. Similarly, transmission electron microscopy analysis (TEM) showed that the foot-process effacement (FPE) was attenuated in Npr3 ΔPOD mice. Proteomics did not identify major alterations in core SD proteins, whereas phosphoproteomics revealed signaling changes promoting cytoskeletal stability and stress resilience. Collectively, these findings identify NPR3 as a potential context dependent regulator of SD function and a candidate target in glomerular disease modulation.