Journal of the American Society of Nephrology : JASN · 2025
Phosphofurin Acidic Cluster Sorting Protein 2 Alleviates Kidney Fibrosis by Inhibiting Tubular Epithelial Cell G2/M Arrest through Cyclin-Dependent Kinase-Like 1.
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Li Chenrui, Liu Yan, Zhao Hao, Xi Yiyun, Liu Chongbin, Luo Shilu, Jiang Na, Yang Ming, Han Yachun, Chen Wei, Li Li, Sun Lin
Аннотация
KEY POINTS: Phosphofurin 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.
BACKGROUND: Kidney 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.
METHODS: PTEC-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.
RESULTS: PACS-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.
CONCLUSIONS: Our 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.
BACKGROUND: Kidney 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.
METHODS: PTEC-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.
RESULTS: PACS-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.
CONCLUSIONS: Our 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.