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WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

ABSTRACT: WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

PROVIDER: PRJNA1008450 | ENA |

REPOSITORIES: ENA

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WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.

2024-02-05 | GSE241502 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

2024-05-19 | GSE267765 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

2024-02-05 | GSE241503 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

Project description:WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

| PRJNA1112817 | ENA

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

Project description:WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

| PRJNA1008456 | ENA

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

Project description:WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

| PRJNA1008461 | ENA

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-05 | GSE241504 | GEO

miR-132 mediates renal fibrosis

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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Project description:Bulk RNA-seq heart left ventricle data from wild type and WWP2 gene mutant mice (after 28 days of angiotensinII treatment)

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WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

Project description:Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac remodelling. Recent evidence implicates monocytes/macrophages modulating cardiac fibrosis but targeting these is convoluted, giving their tissue heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis. Here we focus on the role of WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that its myeloid-specific deletion reduces cardiac fibrosis in hypertension-induced NICM. Using the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase driven by Ccl5-expressing Ly6chigh monocytes. Among other cardiac macrophage subtypes, WWP2 dysfunction primarily affects the Ccl5-dependent infiltration and activation of Ly6chigh monocytes, which causes reduced myofibroblast trans-differentiation. WWP2 interacts with IRF7, promoting its non-degradative monoubiquitination, nuclear translocation and transcriptional activity, including upstream Ccl5. Thus, we identify WWP2 as a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.

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