ArticleJournal of the American Society of Nephrology : JASN2026
Phosphofurin Acidic Cluster Sorting Protein 2 Alleviates Kidney Fibrosis by Inhibiting Tubular Epithelial Cell G2/M Arrest through Cyclin-Dependent Kinase-Like 1.
Article in Journal of the American Society of Nephrology : JASN, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- A New Regulatory Pathway of Cell Cycle Arrest Governs Tubular Cell Fate and Fibrosis Development.Journal of the American Society of Nephrology : JASN · 2026Article
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12 authors.
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Abstract
key pointsPhosphofurin acidic cluster sorting protein 2 (PACS-2) expression was lower in fibrotic kidney tubule, and proximal tubule-specific deficiency accelerated the progression of CKD. PACS-2 deficiency exacerbated G2/M cell cycle arrest in proximal tubular cells to promote kidney fibrosis. PACS-2 interacted with cyclin-dependent kinase-like 1 and modulated its kinase activity, thereby regulating cell cycle progression.
backgroundKidney fibrosis is the final common pathway of CKD. Proximal tubular epithelial cells (PTECs) arrested in G2/M phase of the cell cycle play a pivotal role in kidney fibrosis. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional protein involved in various cellular activities including cell cycle regulation, yet its role in kidney fibrosis remains unclear.
methodsPTEC-specific Pacs-2 knockout mice were generated by using LoxP-Cre recombination system and subjected to unilateral ureteral obstruction (UUO) and aristolochic acid to induce kidney fibrosis. Cultured human and mouse tubular epithelial cells were treated with TGF- β 1 to analyze the underlying cellular mechanisms. Coimmunoprecipitation coupled with mass spectrometry, molecular cloning, and genetic manipulation were used to investigate PACS-2 interactions and specific binding domains.
resultsPACS-2 expression was significantly lower in the cortex of fibrotic kidney from UUO mouse. PACS-2 deficiency in PTECs exacerbated G2/M cell cycle arrest and kidney fibrosis in murine UUO and aristolochic acid nephropathy models, two independent models for CKD. In vitro , overexpression of PACS-2 alleviated TGF- β 1-induced fibrogenic responses in PTECs through inhibiting cell cycle arrest at G2/M phase. By coimmunoprecipitation coupled with mass spectrometry, we identified cyclin-dependent kinase-like 1 (CDKL1) as the key molecule linking PACS-2 to cell cycle progression in PTECs. Knockdown of CDKL1 partially reversed the antifibrotic effects of PACS-2 by promoting G2/M cell cycle arrest in TGF- β 1-stimulated HK-2 cells. Mechanistically, we demonstrated that PACS-2 interacted with kinase domain of CDKL1 and modulated its kinase activity, thereby regulating cell cycle, rather than affecting its subcellular translocation or protein expression.
conclusionsOur study demonstrates that renal tubular PACS-2 alleviated G2/M cell cycle arrest and kidney fibrosis by interacting with CDKL1 and modulating its kinase activity.
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