{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:59:35Z","timestamp":1781650775177,"version":"3.54.5"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chaire Professeur Junior","award":["ANR-25-CPJ1-0134-01"],"award-info":[{"award-number":["ANR-25-CPJ1-0134-01"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pflugers Arch - Eur J Physiol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Transforming growth factor beta (TGF-\u03b2) is a pleiotropic factor that plays a key role in the pathophysiology of chronic kidney disease (CKD). However, targeting TGF-\u03b2 inhibition failed to mitigate CKD in practice. The proximal tubule (PT), the most vulnerable renal segment, plays a central role in post-injury repair or the drift to CKD. Despite its well-documented profibrotic effects, recent studies revealed benefits of TGF-\u03b2 signaling in PT response to CKD, raising the question of its therapeutic potential. This review highlights mechanisms by which TGF-\u03b2 signaling mediates the PT adaptive response to chronic injury and provides perspectives for developing novel CKD therapy.<\/jats:p>","DOI":"10.1007\/s00424-026-03168-x","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:57:50Z","timestamp":1776905870000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proximal TGF-\u03b2 Signaling in Chronic Injury: from a notorious fibrotic factor to a repair ally"],"prefix":"10.1007","volume":"478","author":[{"given":"Stellor","family":"Nlandu Khodo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"issue":"7","key":"3168_CR1","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1038\/onc.2008.454","volume":"28","author":"AA Mourskaia","year":"2009","unstructured":"Mourskaia AA et al (2009) Transforming growth factor-beta1 is the predominant isoform required for breast cancer cell outgrowth in bone. Oncogene 28(7):1005\u20131015","journal-title":"Oncogene"},{"issue":"10","key":"3168_CR2","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrm3434","volume":"13","author":"J Massague","year":"2012","unstructured":"Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13(10):616\u2013630","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"3168_CR3","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/j.1523-1755.2004.00779.x","volume":"66","author":"K Inazaki","year":"2004","unstructured":"Inazaki K et al (2004) Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Kidney Int 66(2):597\u2013604","journal-title":"Kidney Int"},{"issue":"7","key":"3168_CR4","doi-asserted-by":"publisher","first-page":"e00181","DOI":"10.1002\/phy2.181","volume":"1","author":"T Kellenberger","year":"2013","unstructured":"Kellenberger T et al (2013) Differential effects of Smad3 targeting in a murine model of chronic kidney disease. Physiol Rep 1(7):e00181","journal-title":"Physiol Rep"},{"issue":"9","key":"3168_CR5","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1681\/ASN.2009121244","volume":"21","author":"XM Meng","year":"2010","unstructured":"Meng XM et al (2010) Smad2 protects against TGF-beta\/Smad3-mediated renal fibrosis. J Am Soc Nephrol 21(9):1477\u20131487","journal-title":"J Am Soc Nephrol"},{"key":"3168_CR6","doi-asserted-by":"crossref","unstructured":"Nlandu-Khodo S et al (2017) Blocking TGF-beta and beta-Catenin Epithelial Crosstalk Exacerbates CKD. J Am Soc Nephrol. 2017 Jul 12;28(12):3490\u20133503","DOI":"10.1681\/ASN.2016121351"},{"issue":"1","key":"3168_CR7","doi-asserted-by":"publisher","first-page":"3236","DOI":"10.1038\/s41467-023-39050-y","volume":"14","author":"M Kayhan","year":"2023","unstructured":"Kayhan M et al (2023) Intrinsic TGF-\u03b2 signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease. Nat Commun 14(1):3236","journal-title":"Nat Commun"},{"issue":"18","key":"3168_CR8","doi-asserted-by":"publisher","first-page":"4593","DOI":"10.1242\/dev.01324","volume":"131","author":"L Oxburgh","year":"2004","unstructured":"Oxburgh L et al (2004) TGFbeta superfamily signals are required for morphogenesis of the kidney mesenchyme progenitor population. Development 131(18):4593\u20134605","journal-title":"Development"},{"issue":"6","key":"3168_CR9","doi-asserted-by":"publisher","first-page":"F499","DOI":"10.1152\/ajprenal.00446.2015","volume":"310","author":"S Nlandu Khodo","year":"2016","unstructured":"Nlandu Khodo S et al (2016) Deleting the TGF-beta receptor in proximal tubules impairs HGF signaling. Am J Physiol Ren Physiol 310(6):F499\u2013510","journal-title":"Am J Physiol Ren Physiol"},{"issue":"1","key":"3168_CR10","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1038\/s41467-024-46870-z","volume":"15","author":"A Lozovska","year":"2024","unstructured":"Lozovska A et al (2024) Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape. Nat Commun 15(1):2509","journal-title":"Nat Commun"},{"issue":"12","key":"3168_CR11","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1111\/jcmm.12919","volume":"20","author":"SY Choi","year":"2016","unstructured":"Choi SY et al (2016) Class I HDACs specifically regulate E-cadherin expression in human renal epithelial cells. J Cell Mol Med 20(12):2289\u20132298","journal-title":"J Cell Mol Med"},{"issue":"9","key":"3168_CR12","doi-asserted-by":"publisher","first-page":"4612","DOI":"10.4049\/jimmunol.170.9.4612","volume":"170","author":"R Bommireddy","year":"2003","unstructured":"Bommireddy R et al (2003) TGF-beta 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. J Immunol 170(9):4612\u20134622","journal-title":"J Immunol"},{"issue":"2","key":"3168_CR13","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1182\/blood.V100.2.560","volume":"100","author":"P Leveen","year":"2002","unstructured":"Leveen P et al (2002) Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100(2):560\u2013568","journal-title":"Blood"},{"issue":"4","key":"3168_CR14","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.cmet.2019.08.003","volume":"30","author":"KW Chung","year":"2019","unstructured":"Chung KW et al (2019) Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis. Cell Metab 30(4):784\u2013799e5","journal-title":"Cell Metab"},{"issue":"6494","key":"3168_CR15","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/371257a0","volume":"15","author":"GJ Hannon","year":"1994","unstructured":"Hannon GJ, Beach D (1994) INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 15(6494):257\u2013261","journal-title":"Nature"},{"issue":"4","key":"3168_CR16","doi-asserted-by":"publisher","first-page":"F379","DOI":"10.1152\/ajprenal.00475.2013","volume":"306","author":"DP DiRocco","year":"2014","unstructured":"DiRocco DP et al (2014) CDK4\/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am J Physiol Ren Physiol 306(4):F379\u2013F388","journal-title":"Am J Physiol Ren Physiol"},{"issue":"2","key":"3168_CR17","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0092-8674(04)00298-3","volume":"117","author":"J Seoane","year":"2004","unstructured":"Seoane J et al (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117(2):211\u2013223","journal-title":"Cell"},{"issue":"3","key":"3168_CR18","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/ki.2015.51","volume":"88","author":"S Neelisetty","year":"2015","unstructured":"Neelisetty S et al (2015) Renal fibrosis is not reduced by blocking transforming growth factor-beta signaling in matrix-producing interstitial cells. Kidney Int 88(3):503\u2013514","journal-title":"Kidney Int"},{"issue":"8","key":"3168_CR19","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1681\/ASN.2010020147","volume":"21","author":"L Gewin","year":"2010","unstructured":"Gewin L et al (2010) TGF-beta receptor deletion in the renal collecting system exacerbates fibrosis. J Am Soc Nephrol 21(8):1334\u20131343","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"3168_CR20","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1681\/ASN.2015111230","volume":"28","author":"J Voelker","year":"2017","unstructured":"Voelker J et al (2017) Anti-TGF-beta1 Antibody Therapy in Patients with Diabetic Nephropathy. J Am Soc Nephrol 28(3):953\u2013962","journal-title":"J Am Soc Nephrol"}],"container-title":["Pfl\u00fcgers Archiv - European Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-026-03168-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00424-026-03168-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-026-03168-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:35:34Z","timestamp":1781649334000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00424-026-03168-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":20,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["3168"],"URL":"https:\/\/doi.org\/10.1007\/s00424-026-03168-x","relation":{},"ISSN":["0031-6768","1432-2013"],"issn-type":[{"value":"0031-6768","type":"print"},{"value":"1432-2013","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]},"assertion":[{"value":"3 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The author has no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"40"}}