Deletion of Nephrocystin-4 Exacerbates Kidney and Cardiac Function in Mice Cardiorenal Syndrome Model via the Interaction with Itch E3 ligase

Cardiorenal syndrome (CRS), characterized by cardiac and renal dysfunction, is an increasingly common health issue with a high mortality rate. Nephrocystin 4 (NPHP4) is the major reason for end-stage renal disease in children. We have reported that a single nucleotide polymorphism (SNP) in NPHP4 is a genetic risk factor for CRS in the general population. However, the functional role of Nphp4 in CRS development remains unexamined. Systemic Nphp4 knockout (KO) mice were developed by deleting exons 3-8. RNA sequencing of the heart and kidney tissues revealed that the gene sets associated with mitochondrial function were significantly downregulated in Nphp4 KO mice compared with their wild-type (WT) littermates. Furthermore, Nphp4 KO mice exhibited less cardiac hypertrophy but exacerbated kidney and cardiac function compared with the WT mice in the CRS models induced via thoracic transverse aortic constriction and 0.2% adenine-diet. Immunoprecipitation confirmed the interaction between Nphp4 and the HECT-type E3 ligase Itch. Furthermore, we observed that Itch targets Lats2 and insulin-like growth factor-1 receptors in cardiomyocytes. Nphp4 knockdown activated Hippo signaling and worsened mitochondrial function in H9C2 cardiomyocytes by inhibiting Itch-dependent Lats2 degradation. Furthermore, it inhibited insulin-like growth factor-1 signaling by disturbing itch-mediated endosome function. Nphp4 deletion exacerbates kidney and cardiac function in the mouse CRS models via mitochondrial dysfunction. Nphp4 mediates Hippo and insulin-like growth factor-1 signaling by interacting with Itch. Nphp4/Itch axis plays the pathophysiological role in CRS development.