{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:19:34Z","timestamp":1786627174767,"version":"build-2736575974"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81730018"],"award-info":[{"award-number":["81730018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82300828"],"award-info":[{"award-number":["82300828"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82370730"],"award-info":[{"award-number":["82370730"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82400805"],"award-info":[{"award-number":["82400805"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,5]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Phosphofurin acidic cluster sorting protein 2 (PACS-2) expression was lower in fibrotic kidney tubule, and proximal tubule\u2013specific deficiency accelerated the progression of CKD.<\/jats:p>\n <\/jats:list-item>\n \n PACS-2 deficiency exacerbated G2\/M cell cycle arrest in proximal tubular cells to promote kidney fibrosis.<\/jats:p>\n <\/jats:list-item>\n \n PACS-2 interacted with cyclin-dependent kinase-like 1 and modulated its kinase activity, thereby regulating cell cycle progression.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n PTEC-specific\n Pacs-2<\/jats:italic>\n 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-\n \u03b2<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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.\n In vitro<\/jats:italic>\n , overexpression of PACS-2 alleviated TGF-\n \u03b2<\/jats:italic>\n 1\u2013induced 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-\n \u03b2<\/jats:italic>\n 1\u2013stimulated 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000953","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T17:00:18Z","timestamp":1767027618000},"page":"913-927","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Phosphofurin Acidic Cluster Sorting Protein 2 Alleviates Kidney Fibrosis by Inhibiting Tubular Epithelial Cell G2\/M Arrest through Cyclin-Dependent Kinase-Like 1"],"prefix":"10.1681","volume":"37","author":[{"given":"Chenrui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5451-0338","authenticated-orcid":false,"given":"Chongbin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1698-0616","authenticated-orcid":false,"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yachun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-0822","authenticated-orcid":false,"given":"Lin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, 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