{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:35:56Z","timestamp":1791286556405,"version":"4.1.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:p>Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.<\/jats:p>","DOI":"10.1681\/asn.2015050500","type":"journal-article","created":{"date-parts":[[2015,11,4]],"date-time":"2015-11-04T23:00:06Z","timestamp":1446678006000},"page":"1943-1957","source":"Crossref","is-referenced-by-count":39,"title":["Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model"],"prefix":"10.1681","volume":"27","author":[{"given":"Wenqing","family":"Yin","sequence":"first","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said Movahedi","family":"Naini","sequence":"additional","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochun","family":"Chen","sequence":"additional","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk M.","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"Humphreys","sequence":"additional","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"},{"name":"Harvard Stem Cell Institute, Cambridge, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph V.","family":"Bonventre","sequence":"additional","affiliation":[{"name":"Renal Division, Brigham and Women\u2019s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;"},{"name":"Harvard Stem Cell Institute, Cambridge, Massachusetts; and"},{"name":"Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,11,4]]},"reference":[{"key":"B1-20231016","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1074\/jbc.273.7.4135","article-title":"Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.","volume":"273","author":"Ichimura","year":"1998","journal-title":"J Biol Chem"},{"key":"B2-20231016","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1172\/JCI34487","article-title":"Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells.","volume":"118","author":"Ichimura","year":"2008","journal-title":"J Clin Invest"},{"key":"B3-20231016","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nature06307","article-title":"Identification of Tim4 as a phosphatidylserine receptor.","volume":"450","author":"Miyanishi","year":"2007","journal-title":"Nature"},{"key":"B4-20231016","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.immuni.2007.11.011","article-title":"TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells.","volume":"27","author":"Kobayashi","year":"2007","journal-title":"Immunity"},{"key":"B5-20231016","doi-asserted-by":"crossref","first-page":"F456","DOI":"10.1152\/ajprenal.00403.2005","article-title":"Tubular kidney injury molecule-1 in protein-overload nephropathy.","volume":"291","author":"van Timmeren","year":"2006","journal-title":"Am J Physiol Renal Physiol"},{"key":"B6-20231016","doi-asserted-by":"crossref","first-page":"F1136","DOI":"10.1152\/ajprenal.00541.2007","article-title":"Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time.","volume":"296","author":"Kramer","year":"2009","journal-title":"Am J Physiol Renal Physiol"},{"key":"B7-20231016","doi-asserted-by":"crossref","first-page":"F313","DOI":"10.1152\/ajprenal.00180.2006","article-title":"Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase.","volume":"292","author":"de Borst","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"key":"B8-20231016","doi-asserted-by":"crossref","first-page":"F1326","DOI":"10.1152\/ajprenal.00166.2002","article-title":"Kidney injury molecule-1 expression in murine polycystic kidney disease.","volume":"283","author":"Kuehn","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"key":"B9-20231016","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/path.2175","article-title":"Tubular kidney injury molecule-1 (KIM-1) in human renal disease.","volume":"212","author":"van Timmeren","year":"2007","journal-title":"J Pathol"},{"key":"B10-20231016","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/path.2642","article-title":"Kidney injury molecule-1 in renal disease.","volume":"220","author":"Waanders","year":"2010","journal-title":"J Pathol"},{"key":"B11-20231016","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1681\/ASN.2009040390","article-title":"Tubular expression of KIM-1 does not predict delayed function after transplantation.","volume":"21","author":"Schr\u00f6ppel","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"B12-20231016","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1172\/JCI45361","article-title":"Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis.","volume":"123","author":"Humphreys","year":"2013","journal-title":"J Clin Invest"},{"key":"B13-20231016","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1126\/science.1066652","article-title":"Genomics. 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