WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. WWP2 uncouples the profibrotic activation and cell proliferation in renal Show more
WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. WWP2 uncouples the profibrotic activation and cell proliferation in renal myofibroblasts. WWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Renal fibrosis is a common pathologic end point in CKD that is challenging to reverse, and myofibroblasts are responsible for the accumulation of a fibrillar collagen–rich extracellular matrix. Recent studies have unveiled myofibroblasts' diversity in proliferative and fibrotic characteristics, which are linked to different metabolic states. We previously demonstrated the regulation of extracellular matrix genes and tissue fibrosis by WWP2, a multifunctional E3 ubiquitin–protein ligase. Here, we investigate WWP2 in renal fibrosis and in the metabolic reprograming of myofibroblasts in CKD. We used kidney samples from patients with CKD and The tubulointerstitial expression of WWP2 was associated with fibrotic progression in patients with CKD and in murine kidney disease models. WWP2 deficiency promoted myofibroblast proliferation and halted profibrotic activation, reducing the severity of renal fibrosis WWP2 regulates the metabolic reprogramming of profibrotic myofibroblasts by a WWP2-PGC-1 Show less
Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monoc Show more
Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6c Show less