{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T22:05:21Z","timestamp":1790546721506,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Natural Science Foundation","award":["2020A1515010286"],"award-info":[{"award-number":["2020A1515010286"]}]},{"name":"Guangdong Natural Science Foundation","award":["2022A1515012307"],"award-info":[{"award-number":["2022A1515012307"]}]},{"name":"Guangdong Natural Science Foundation","award":["SCE093DS"],"award-info":[{"award-number":["SCE093DS"]}]},{"name":"Guangdong Natural Science Foundation","award":["2020C012"],"award-info":[{"award-number":["2020C012"]}]},{"name":"Beijing Bethune Public Welfare Foundation","award":["2020A1515010286"],"award-info":[{"award-number":["2020A1515010286"]}]},{"name":"Beijing Bethune Public Welfare Foundation","award":["2022A1515012307"],"award-info":[{"award-number":["2022A1515012307"]}]},{"name":"Beijing Bethune Public Welfare Foundation","award":["SCE093DS"],"award-info":[{"award-number":["SCE093DS"]}]},{"name":"Beijing Bethune Public Welfare Foundation","award":["2020C012"],"award-info":[{"award-number":["2020C012"]}]},{"name":"President Foundation of Nanfang Hospital, Southern Medical University","award":["2020A1515010286"],"award-info":[{"award-number":["2020A1515010286"]}]},{"name":"President Foundation of Nanfang Hospital, Southern Medical University","award":["2022A1515012307"],"award-info":[{"award-number":["2022A1515012307"]}]},{"name":"President Foundation of Nanfang Hospital, Southern Medical University","award":["SCE093DS"],"award-info":[{"award-number":["SCE093DS"]}]},{"name":"President Foundation of Nanfang Hospital, Southern Medical University","award":["2020C012"],"award-info":[{"award-number":["2020C012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1KO) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1KD) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and \u03b1-smooth muscle actin (\u03b1-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1KO mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of \u03b1-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1KD HK2 cells. Thus, the GEF-H1\/RhoA\/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms24043504","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T02:56:13Z","timestamp":1675997773000},"page":"3504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1204-6404","authenticated-orcid":false,"given":"Qiulei","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3214-1233","authenticated-orcid":false,"given":"Jiayong","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huamu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-8626","authenticated-orcid":false,"given":"Liangzhong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1681\/ASN.2008050456","article-title":"Nephronophthisis: Disease Mechanisms of a Ciliopathy","volume":"20","author":"Hildebrandt","year":"2009","journal-title":"J. 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