Loss of PCAF in proximal tubular cells exacerbates renal fibrosis by promoting partial epithelial-to-mesenchymal transition
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Renal fibrosis is a consequence of chronic kidney disease, which is estimated to affect 10–14% of the global population. The molecular mechanisms in the pathogenesis of renal fibrosis are still unclear, and there is a lack of effective therapies. Here we identified decreased levels of p300/CBP-associated factor (PCAF) in kidney tissues with fibrosis and demonstrated that PCAF-specific knockout in proximal tubular cells accelerates renal fibrosis in both unilateral ureteral obstruction surgery and folic acid-induced models. Conversely, overexpressing PCAF in the kidney using adenovirus mitigated unilateral ureteral obstruction-induced renal fibrosis. Importantly, PCAF inhibits the epithelial-to-mesenchymal transition of proximal tubular cells by transcriptionally activating adherens junction genes. Moreover, we observed that TGF-β signaling induces lysosomal degradation of PCAF, suggesting that PCAF reduction is affected in the fibrotic milieu. These findings confirm that PCAF is a negative regulator of renal fibrosis and suggest that it could serve as a novel therapeutic target for patients with chronic kidney disease.
Abstract
Renal fibrosis is a consequence of chronic kidney disease, which is estimated to affect 10–14% of the global population. The molecular mechanisms in the pathogenesis of renal fibrosis are still unclear, and there is a lack of effective therapies. Here we identified decreased levels of p300/CBP-associated factor (PCAF) in kidney tissues with fibrosis and demonstrated that PCAF-specific knockout in proximal tubular cells accelerates renal fibrosis in both unilateral ureteral obstruction surgery and folic acid-induced models. Conversely, overexpressing PCAF in the kidney using adenovirus mitigated unilateral ureteral obstruction-induced renal fibrosis. Importantly, PCAF inhibits the epithelial-to-mesenchymal transition of proximal tubular cells by transcriptionally activating adherens junction genes. Moreover, we observed that TGF-β signaling induces lysosomal degradation of PCAF, suggesting that PCAF reduction is affected in the fibrotic milieu. These findings confirm that PCAF is a negative regulator of renal fibrosis and suggest that it could serve as a novel therapeutic target for patients with chronic kidney disease.