WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts

Abstract Renal fibrosis is a common pathological endpoint in chronic kidney disease (CKD) that is challenging to reverse. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM) in fibrotic kidney, recent studies have unveiled their diversity in terms of proliferative and fibrotic characteristics. This diversity could be linked with the existence of different metabolic states, and myofibroblast metabolic reprogramming may contribute to the pathogenesis and progression of renal fibrosis. Here, we reveal an unexpected role of the E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of myofibroblasts during renal fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients, and in pre-clinical murine models of CKD. WWP2 deficiency increases fatty acid oxidation and activates the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. This concurrently promotes myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis. Mechanistically, WWP2 suppresses the transcription of PGC-1α, a metabolic mediator shaping myofibroblast fibrotic response. Pharmacological interventions targeting PGC-1α reverse the effects of WWP2 on fibrotic myofibroblasts. These findings demonstrate the influence of WWP2 on essential metabolic pathways involved in fibrogenesis, uncovering the WWP2-PGC-1α axis that orchestrates the metabolic reprogramming of myofibroblasts during renal fibrosis. Our study presents a potential novel target for therapeutic intervention in the treatment of chronic kidney disease. Graphical abstract Highlights WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. WWP2 uncouples the pro-fibrotic activation and cell proliferation in renal myofibroblasts. WWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator PGC-1α Myofibroblast metabolic reprogramming mediates the effect of WWP2 on fibrotic myofibroblasts.