WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts

作者：Huimei Chen, Ran You, Jing Guo, Wei Zhou, Gabriel Chew, Nithya Devapragash, Jui Zhi Loh, Loreto Gesualdo, Yanwei Li, Yuteng Jiang, Elisabeth Li Sa Tan, Shuang Chen, Paola Pontrelli, Francesco Pesce, Jacques Behmoaras, Aihua Zhang, Enrico Petretto · 发表于：Journal of the American Society of Nephrology · 年份：2024 · DOI：10.1681/asn.0000000000000328 · 被引用次数：36 · 研究领域：Chronic Kidney Disease and Diabetes、Aortic aneurysm repair treatments、Dialysis and Renal Disease Management

Key Points 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. Background 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. Methods We used kidney samples from patients with CKD and WWP2 -null kidney disease mice models and leveraged single-cell RNA sequencing analysis to detail the cell-specific regulation of WWP2 in fibrotic kidneys. Experiments in primary cultured myofibroblasts by bulk-RNA sequencing, chromatin immunoprecipitation sequencing, metabolomics, and cellular metabolism assays were used to study the metabolic regulation of WWP2 and its downstream signaling. Results The tubulointerstitial expression of ...