{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:08:03Z","timestamp":1773662883018,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Municipal Science and Technology Major Project","award":["2023SHZDZX02C09"],"award-info":[{"award-number":["2023SHZDZX02C09"]}]},{"name":"Shanghai Municipal Science and Technology \u201cInnovation Action Plan\u201d Basic Research Field Project","award":["23JC1401200"],"award-info":[{"award-number":["23JC1401200"]}]},{"name":"National Key Research and Development Programme","award":["2021YFC2500202"],"award-info":[{"award-number":["2021YFC2500202"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talents\u201d Youth Medical Program","award":["2023_70"],"award-info":[{"award-number":["2023_70"]}]},{"name":"Shanghai Medical Health Clinical Research Youth Program","award":["20244Y0024"],"award-info":[{"award-number":["20244Y0024"]}]},{"name":"National Natural Sciences Foundation of China for Young Scholars","award":["81900602"],"award-info":[{"award-number":["81900602"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with nephronophthisis caused by nephrocystin 3 (NPHP3) variants rapidly progress to end-stage kidney disease. However, existing Nphp3 mouse models fail to fully recapitulate the characteristics of this disease. We generated a renal tubule-specific Nphp3 knockout mouse model that more accurately mirrors the human disease course. The mouse model was first validated by confirming the loss of Nphp3 protein expression in renal tubules. Comprehensive phenotypic analyses were then performed to assess both renal and extrarenal manifestations. The origin of renal cysts was investigated, and the underlying mechanisms were further validated. We successfully generated a renal tubule-specific Nphp3 knockout mouse model (Cdh16-Cre; Nphp3flox\/flox). These mice exhibited a markedly shortened lifespan (5\u20138 weeks) and developed key features of infantile nephronophthisis, including early-onset renal cysts originating from distal tubules and collecting ducts, progressive interstitial fibrosis that was evident by postnatal week 2, a rapid decline in kidney function, and increased urinary protein levels. Importantly, treatment with the vasopressin V2 receptor antagonist tolvaptan or the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040) significantly attenuated cyst growth and improved kidney morphology, confirming shared pathogenic pathways with other Nphp3 models. We established a renal tubule-specific Nphp3 knockout mouse model that accurately recapitulates the aggressive infantile form of nephronophthisis characterized by early cystogenesis, progressive fibrosis, and a shortened lifespan, and is ideal for evaluating novel interventions against this currently untreatable ciliopathy.<\/jats:p>","DOI":"10.3390\/ijms27062687","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:10:43Z","timestamp":1773655843000},"page":"2687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Renal Tubule-Specific Deletion of Nephrocystin 3 (Nphp3) Causes Infantile Nephronophthisis-like Phenotypes in Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Xuanjin","family":"Du","sequence":"first","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gangqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"},{"name":"National Key Laboratory of Kidney Diseases, Beijing 100853, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoshan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai 201102, China"},{"name":"Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai 201102, China"},{"name":"National Key Laboratory of Kidney Diseases, Beijing 100853, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1136\/jmg.2010.082552","article-title":"Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy","volume":"48","author":"Otto","year":"2011","journal-title":"J. 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