{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T10:09:30Z","timestamp":1774778970005,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2024YFC3406700"],"award-info":[{"award-number":["2024YFC3406700"]}]},{"name":"National Key Research and Development Program of China","award":["2024YFC3406705"],"award-info":[{"award-number":["2024YFC3406705"]}]},{"name":"National Key Research and Development Program of China","award":["2022YFC2705100"],"award-info":[{"award-number":["2022YFC2705100"]}]},{"name":"National Key Research and Development Program of China","award":["2022YFC2705105"],"award-info":[{"award-number":["2022YFC2705105"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01h0zpd94","doi-asserted-by":"publisher","award":["82470707"],"award-info":[{"award-number":["82470707"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai \u201cScience and Technology Innovation Action Plan\u201d","award":["22YF1403600"],"award-info":[{"award-number":["22YF1403600"]}]},{"name":"Children\u2019s Hospital of Fudan University Clinical and Basic \u201cDual-Pairing\u201d Initiative","award":["EKSJD202411"],"award-info":[{"award-number":["EKSJD202411"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital anomalies of the kidney and urinary tract (CAKUT) constitute the most common underlying cause of chronic kidney disease in pediatric populations. Maternal hypovitaminosis D links to mesoderm-related birth defects, leading to our hypothesis that maternal vitamin D deficiency (VDD) impairs renal development (a mesoderm-derived process) and induces offspring CAKUT. To investigate whether a low-vitamin D level can cause CAKUT, we used vitamin D-free diets to induce a maternal vitamin D deficiency mice model. The maternal vitamin D deficiency (VDD) mice models and normal vitamin D status (CON) were successfully established by administering a vitamin D-free or vitamin D-sufficient diet for 4 weeks prior to pregnancy. The overall incidence of CAKUT was significantly increased in VDD neonatal mice (19.4% vs. 2.44%; p = 0.0006), with a higher incidence of early duplicated budding in E11.5. E11.5 ureteric bud tissue revealed significantly increased activity of Gdnf-Ret-p-Erk1\/2 signaling in the VDD group. In vivo intervention with the p-Erk1\/2 antagonist U0126 in the pregnant VDD mice model at E10.5 improved CAKUT occurrence in offspring with p-Erk1\/2 expression decreasing toward normal levels. Early metanephric ureteric bud H3K4me3 CUT&amp;TAG analysis at E12.5 revealed chromatin activation patterns, which revealed that the downregulation of Hnf1\u03b2 promoter region peaks was accompanied by reduced Hnf1\u03b2 expression, and Robo2 promoter region peak was upregulated with increased Robo2 expression in the VDD group. Maternal vitamin D deficiency in mice significantly increased offspring CAKUT incidence. This phenotype was mediated by enhanced Gdnf-Ret-p-Erk1\/2 signaling and reversed by p-Erk1\/2 inhibition, with VDD inducing epigenetic remodeling of Hnf1\u03b2 and Robo2 promoters.<\/jats:p>","DOI":"10.3390\/ijms27073042","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"3042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vitamin D Deficiency Activates Gdnf-Ret-pErk1\/2 Signal and Induces Kidney Malformations in Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Minghui","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningli","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haixin","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianfan","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical 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, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rufeng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohui","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China"},{"name":"Laboratory Animal Center, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical Center, Shanghai 201102, China"},{"name":"National Key Laboratory of Kidney Diseases, Beijing 100853, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-6737","authenticated-orcid":false,"given":"Qian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children\u2019s Hospital of Fudan University, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, National Children\u2032s Medical 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":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1046\/j.1523-1755.2002.00086.x","article-title":"Toward an etiological classi cation of developmental disorders of the kidney and upper urinary tract","volume":"61","author":"Pohl","year":"2002","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s00404-001-0265-4","article-title":"Malformations in newborn: Results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system 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