{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:16:58Z","timestamp":1773299818870,"version":"3.50.1"},"reference-count":36,"publisher":"The Company of Biologists","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remained unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrated that miR-34a was markedly up-regulated in tubulointerstitial spaces and microvesicles isolated from kidney. However, the increased miR-34a was not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubated with TGF-\u03b21. MiR-34a was markedly up-regulated in microvesicles isolated from cell culture media of TGF-\u03b21 treated fibroblasts. These microvesicles acted as a vector for delivery of up-regulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induced apoptosis of tubular cells. The exogenous miR-34a regulated tubular apoptosis by modulating the expression of anti-apoptotic protein Bcl-2. Moreover, injection of exogenous miR-34a-containing microvesicles enhanced tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructive kidney. This study provided a new mechanism concerning microvesicle-mediated fibroblast-to-tubular cell communication of miRNA in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis.<\/jats:p>","DOI":"10.1242\/jcs.155523","type":"journal-article","created":{"date-parts":[[2014,8,9]],"date-time":"2014-08-09T04:42:48Z","timestamp":1407559368000},"source":"Crossref","is-referenced-by-count":29,"title":["Secreted fibroblast miR-34a induces tubular cell apoptosis in fibrotic kidney"],"prefix":"10.1242","author":[{"given":"Yang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxia","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weifang","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Zen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunsun","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junwei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2021042613422396000_b1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000402883","article-title":"The role of the interstitium of the renal cortex in renal disease.","volume":"16","author":"Bohle","year":"1979","journal-title":"Contrib. Nephrol."},{"key":"2021042613422396000_b2","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1016\/j.cub.2007.06.068","article-title":"p53-mediated activation of miRNA34 candidate tumor-suppressor genes.","volume":"17","author":"Bommer","year":"2007","journal-title":"Curr. Biol."},{"key":"2021042613422396000_b3","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1681\/ASN.2012101031","article-title":"TGF-\u03b21-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis.","volume":"24","author":"Borges","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042613422396000_b4","doi-asserted-by":"publisher","first-page":"15237","DOI":"10.1074\/jbc.274.21.15237","article-title":"p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor.","volume":"274","author":"Budhram-Mahadeo","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021042613422396000_b5","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.4049\/jimmunol.139.9.2906","article-title":"Heymann antibodies induce complement-dependent injury of rat glomerular visceral epithelial cells.","volume":"139","author":"Camussi","year":"1987","journal-title":"J. Immunol."},{"key":"2021042613422396000_b6","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1038\/ki.2010.278","article-title":"Exosomes\/microvesicles as a mechanism of cell-to-cell communication.","volume":"78","author":"Camussi","year":"2010","journal-title":"Kidney Int."},{"key":"2021042613422396000_b7","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1242\/jcs.032029","article-title":"The regulated exocytosis of enlargeosomes is mediated by a SNARE machinery that includes VAMP4.","volume":"121","author":"Cocucci","year":"2008","journal-title":"J. Cell Sci."},{"key":"2021042613422396000_b8","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1158\/1541-7786.MCR-07-2102","article-title":"A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene.","volume":"6","author":"Cole","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"2021042613422396000_b9","doi-asserted-by":"publisher","first-page":"12537","DOI":"10.1074\/jbc.M300777200","article-title":"Transforming growth factor-beta1 potentiates renal tubular epithelial cell death by a mechanism independent of Smad signaling.","volume":"278","author":"Dai","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042613422396000_b10","doi-asserted-by":"publisher","first-page":"F4","DOI":"10.1152\/ajprenal.00045.2005","article-title":"Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction.","volume":"290","author":"Docherty","year":"2006","journal-title":"Am. J. Physiol."},{"key":"2021042613422396000_b11","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1111\/j.1523-1755.2002.kid579.x","article-title":"Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.","volume":"62","author":"Gao","year":"2002","journal-title":"Kidney Int."},{"key":"2021042613422396000_b12","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/cdd.2009.56","article-title":"The miR-34 family in cancer and apoptosis.","volume":"17","author":"Hermeking","year":"2010","journal-title":"Cell Death Differ."},{"key":"2021042613422396000_b13","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1016\/j.biomaterials.2012.12.016","article-title":"Cationic microRNA-delivering nanovectors with bifunctional peptides for efficient treatment of PANC-1 xenograft model.","volume":"34","author":"Hu","year":"2013","journal-title":"Biomaterials"},{"key":"2021042613422396000_b14","doi-asserted-by":"publisher","first-page":"2668","DOI":"10.1002\/ijc.27549","article-title":"Delta-tocotrienol suppresses Notch-1 pathway by upregulating miR-34a in nonsmall cell lung cancer cells.","volume":"131","author":"Ji","year":"2012","journal-title":"Int. J. Cancer"},{"key":"2021042613422396000_b15","doi-asserted-by":"publisher","first-page":"3893","DOI":"10.1096\/fj.12-214189","article-title":"Apoptosis and angiogenesis: an evolving mechanism for fibrosis.","volume":"27","author":"Johnson","year":"2013","journal-title":"FASEB J."},{"key":"2021042613422396000_b16","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s10549-011-1424-3","article-title":"miRNA-34a is associated with docetaxel resistance in human breast cancer cells.","volume":"131","author":"Kastl","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"2021042613422396000_b17","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.juro.2006.03.076","article-title":"Angiotensin receptor blockade decreases fibrosis and fibroblast expression in a rat model of unilateral ureteral obstruction.","volume":"176","author":"Kellner","year":"2006","journal-title":"J. Urol."},{"key":"2021042613422396000_b18","doi-asserted-by":"publisher","first-page":"3193","DOI":"10.1158\/0008-5472.CAN-07-2780","article-title":"Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence.","volume":"68","author":"Kumamoto","year":"2008","journal-title":"Cancer Res."},{"key":"2021042613422396000_b19","doi-asserted-by":"publisher","first-page":"F7","DOI":"10.1152\/ajprenal.00451.2003","article-title":"Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action.","volume":"287","author":"Liu","year":"2004","journal-title":"Am. J. Physiol."},{"key":"2021042613422396000_b20","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1681\/ASN.2008121226","article-title":"New insights into epithelial-mesenchymal transition in kidney fibrosis.","volume":"21","author":"Liu","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042613422396000_b21","doi-asserted-by":"publisher","first-page":"221","DOI":"10.7150\/ijbs.7.221","article-title":"MiR-34a in age and tissue related radio-sensitivity and serum miR-34a as a novel indicator of radiation injury.","volume":"7","author":"Liu","year":"2011","journal-title":"Int. J. Biol. Sci."},{"key":"2021042613422396000_b22","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.4161\/cc.7.16.6533","article-title":"Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer.","volume":"7","author":"Lodygin","year":"2008","journal-title":"Cell Cycle"},{"key":"2021042613422396000_b23","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1097\/CCO.0b013e32835b7c81","article-title":"Tumor-cell-derived microvesicles as carriers of molecular information in cancer.","volume":"25","author":"Martins","year":"2013","journal-title":"Curr. Opin. Oncol."},{"key":"2021042613422396000_b24","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1046\/j.1523-1755.2000.00414.x","article-title":"Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction.","volume":"58","author":"Miyajima","year":"2000","journal-title":"Kidney Int."},{"key":"2021042613422396000_b25","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1046\/j.1523-1755.2001.0590041304.x","article-title":"Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy.","volume":"59","author":"Mizuno","year":"2001","journal-title":"Kidney Int."},{"key":"2021042613422396000_b26","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1681\/ASN.V13suppl_1s14","article-title":"Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function.","volume":"13","author":"Morrissey","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042613422396000_b27","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1080\/10428190902763517","article-title":"MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes.","volume":"50","author":"Mraz","year":"2009","journal-title":"Leuk. Lymphoma"},{"key":"2021042613422396000_b28","doi-asserted-by":"publisher","first-page":"e24099","DOI":"10.1371\/journal.pone.0024099","article-title":"Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells.","volume":"6","author":"Nalls","year":"2011","journal-title":"PLoS ONE"},{"key":"2021042613422396000_b29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.yjmcc.2013.01.018","article-title":"FAT10 protects cardiac myocytes against apoptosis.","volume":"59","author":"Peng","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021042613422396000_b30","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1093\/intimm\/dxh300","article-title":"Mortalin\/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis.","volume":"17","author":"Pilzer","year":"2005","journal-title":"Int. Immunol."},{"key":"2021042613422396000_b31","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri855","article-title":"Exosomes: composition, biogenesis and function.","volume":"2","author":"Th\u00e9ry","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2021042613422396000_b32","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/S0002-9440(10)62533-3","article-title":"Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis.","volume":"159","author":"Yang","year":"2001","journal-title":"Am. J. Pathol."},{"key":"2021042613422396000_b33","doi-asserted-by":"publisher","DOI":"10.7785\/tcrt.2012.500364","article-title":"MicroRNA-34a Targets Bcl-2 and Sensitizes Human Hepatocellular Carcinoma Cells to Sorafenib Treatment.","author":"Yang","year":"2013","journal-title":"Technol. Cancer Res. Treat"},{"key":"2021042613422396000_b34","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1159\/000052597","article-title":"Role of apoptosis and Bcl-2\/Bax in the development of tubulointerstitial fibrosis during experimental obstructive nephropathy.","volume":"9","author":"Zhang","year":"2001","journal-title":"Exp. Nephrol."},{"key":"2021042613422396000_b35","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.molcel.2010.06.010","article-title":"Secreted monocytic miR-150 enhances targeted endothelial cell migration.","volume":"39","author":"Zhang","year":"2010","journal-title":"Mol. Cell"},{"key":"2021042613422396000_b36","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1016\/j.ajpath.2013.06.032","article-title":"miR-21-containing microvesicles from injured tubular epithelial cells promote tubular phenotype transition by targeting PTEN protein.","volume":"183","author":"Zhou","year":"2013","journal-title":"Am. J. Pathol."}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/127\/20\/4494\/1936249\/jcs-127-20-4494.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.155523\/2046871\/jcs155523.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.155523\/2046871\/jcs155523.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T21:00:50Z","timestamp":1689454850000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/doi\/10.1242\/jcs.155523\/259069\/Secreted-fibroblast-miR-34a-induces-tubular-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,1]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1242\/jcs.155523","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2014,1,1]]},"article-number":"jcs.155523"}}