{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:55:56Z","timestamp":1776102956421,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T00:00:00Z","timestamp":1591228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000738","name":"US Department of Veterans Affairs","doi-asserted-by":"crossref","award":["I01BX02650"],"award-info":[{"award-number":["I01BX02650"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK95835"],"award-info":[{"award-number":["R01DK95835"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015502","name":"Dialysis Clinic Inc.","doi-asserted-by":"publisher","award":["2019-03"],"award-info":[{"award-number":["2019-03"]}],"id":[{"id":"10.13039\/100015502","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>We have shown that the CXCL16\/CXCR6 axis plays a critical role in recruiting inflammatory cells and bone marrow-derived fibroblasts into the kidney leading to renal injury and fibrosis. However, the underlying signaling mechanisms are not known.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In the present study, we examined the role of phosphoinositide-3 kinase \u03b3 (PI3K\u03b3) signaling in the recruitment of inflammatory cells and bone marrow-derived fibroblasts into the kidney and development of renal injury and fibrosis in an experimental model of hypertension induced by angiotensin II.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Blood pressure was comparable between wild-type (WT) and PI3K\u03b3 knockout (KO) mice at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between WT and PI3K\u03b3 KO mice. Compared with WT mice, PI3K\u03b3 KO mice were protected from angiotensin II-induced renal dysfunction and injury and developed less proteinuria. PI3K\u03b3 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidney and inhibited total collagen deposition and extracellular matrix protein production in the kidney in response to angiotensin II. PI3K\u03b3 deficiency inhibited the infiltration of F4\/80+ macrophages and CD3+ T cells into the kidney and reduced gene expression levels of pro-inflammatory cytokines in the kidney following angiotensin II treatment. Finally, inhibition of PI3K\u03b3 suppressed CXCL16-induced monocyte migration in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results indicate that PI3K\u03b3 mediates the influx of macrophages, T cells and bone marrow-derived fibroblasts into the kidney resulting in kidney injury and fibrosis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfaa062","type":"journal-article","created":{"date-parts":[[2020,3,7]],"date-time":"2020-03-07T12:27:31Z","timestamp":1583584051000},"page":"1491-1500","source":"Crossref","is-referenced-by-count":25,"title":["Phosphoinositide 3-kinase \u03b3 deficiency attenuates kidney injury and fibrosis in angiotensin II\u2013induced hypertension"],"prefix":"10.1093","volume":"35","author":[{"given":"Changlong","family":"An","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Wen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William E","family":"Mitch","sequence":"additional","affiliation":[{"name":"Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA"},{"name":"Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA"},{"name":"Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT, USA"},{"name":"Renal Section, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,4]]},"reference":[{"key":"2021020415161028800_gfaa062-B1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/jhh.2013.55","article-title":"Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage","volume":"28","author":"Mennuni","year":"2014","journal-title":"J Hum Hypertens"},{"key":"2021020415161028800_gfaa062-B2","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/nrneph.2011.149","article-title":"Cellular and molecular mechanisms of renal fibrosis","volume":"7","author":"Liu","year":"2011","journal-title":"Nat Rev Nephrol"},{"key":"2021020415161028800_gfaa062-B3","doi-asserted-by":"crossref","first-page":"F515","DOI":"10.1152\/ajprenal.00527.2007","article-title":"Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension","volume":"295","author":"Crowley","year":"2008","journal-title":"Am J Physiol Renal Physiol"},{"key":"2021020415161028800_gfaa062-B4","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1084\/jem.20070657","article-title":"Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction","volume":"204","author":"Guzik","year":"2007","journal-title":"J Exp Med"},{"key":"2021020415161028800_gfaa062-B5","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1161\/CIRCRESAHA.116.303697","article-title":"Inflammation, immunity, and hypertensive end-organ damage","volume":"116","author":"McMaster","year":"2015","journal-title":"Circ Res"},{"key":"2021020415161028800_gfaa062-B6","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.3109\/07853890.2011.653396","article-title":"Immune mechanisms in angiotensin II-induced target-organ damage","volume":"44(Suppl 1","author":"Luft","year":"2012","journal-title":"Ann Med"},{"key":"2021020415161028800_gfaa062-B7","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1146\/annurev.pharmtox.42.091901.115838","article-title":"Structure, function, and inhibition of chemokines","volume":"42","author":"Fernandez","year":"2002","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2021020415161028800_gfaa062-B8","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1161\/HYPERTENSIONAHA.113.01837","article-title":"Critical role of CXCL16 in hypertensive kidney injury and fibrosis","volume":"62","author":"Xia","year":"2013","journal-title":"Hypertension"},{"key":"2021020415161028800_gfaa062-B9","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1161\/ATVBAHA.113.303172","article-title":"CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis","volume":"34","author":"Xia","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2021020415161028800_gfaa062-B10","doi-asserted-by":"crossref","first-page":"28715","DOI":"10.1038\/srep28715","article-title":"CXCL16 deficiency attenuates renal injury and fibrosis in salt-sensitive hypertension","volume":"6","author":"Liang","year":"2016","journal-title":"Sci Rep"},{"key":"2021020415161028800_gfaa062-B11","doi-asserted-by":"crossref","first-page":"H815","DOI":"10.1152\/ajpheart.00948.2015","article-title":"CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis","volume":"311","author":"Ma","year":"2016","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2021020415161028800_gfaa062-B12","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrm2882","article-title":"The emerging mechanisms of isoform-specific PI3K signalling","volume":"11","author":"Vanhaesebroeck","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2021020415161028800_gfaa062-B13","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.jgg.2015.03.003","article-title":"The PI3K\/AKT pathway and renal cell carcinoma","volume":"42","author":"Guo","year":"2015","journal-title":"J Genet Genomics"},{"key":"2021020415161028800_gfaa062-B14","doi-asserted-by":"crossref","first-page":"31059","DOI":"10.1074\/jbc.M113.508234","article-title":"p87 and p101 subunits are distinct regulators determining class IB phosphoinositide 3-kinase (PI3K) specificity","volume":"288","author":"Shymanets","year":"2013","journal-title":"J Biol Chem"},{"key":"2021020415161028800_gfaa062-B15","doi-asserted-by":"crossref","first-page":"ra27","DOI":"10.1126\/scisignal.2000259","article-title":"PI3K\u03b3 adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3\u00a0pools in mast cells","volume":"2","author":"Bohnacker","year":"2009","journal-title":"Sci Signal"},{"key":"2021020415161028800_gfaa062-B16","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1126\/science.287.5455.1049","article-title":"Central role for G protein-coupled phosphoinositide 3-kinase \u03b3 in inflammation","volume":"287","author":"Hirsch","year":"2000","journal-title":"Science"},{"key":"2021020415161028800_gfaa062-B17","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1126\/science.287.5455.1040","article-title":"Function of PI3K\u03b3 in thymocyte development, T cell activation, and neutrophil migration","volume":"287","author":"Sasaki","year":"2000","journal-title":"Science"},{"key":"2021020415161028800_gfaa062-B18","doi-asserted-by":"crossref","first-page":"4475","DOI":"10.4049\/jimmunol.170.9.4475","article-title":"Phosphatidylinositol 3-kinase regulates the CD4\/CD8 T cell differentiation ratio","volume":"170","author":"Rodriguez-Borlado","year":"2003","journal-title":"J Immunol"},{"key":"2021020415161028800_gfaa062-B19","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1126\/science.287.5455.1046","article-title":"Roles of PLC-\u03b2 2 and -\u03b2 3 and PI3K\u03b3 in chemoattractant-mediated signal transduction","volume":"287","author":"Li","year":"2000","journal-title":"Science"},{"key":"2021020415161028800_gfaa062-B20","doi-asserted-by":"crossref","first-page":"H538","DOI":"10.1152\/ajpheart.01114.2010","article-title":"CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis","volume":"301","author":"Xu","year":"2011","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2021020415161028800_gfaa062-B21","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1172\/JCI112924","article-title":"Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis","volume":"79","author":"May","year":"1987","journal-title":"J Clin Invest"},{"key":"2021020415161028800_gfaa062-B22","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1681\/ASN.2010080881","article-title":"CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis","volume":"22","author":"Chen","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"2021020415161028800_gfaa062-B23","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1681\/ASN.2013030217","article-title":"Adiponectin promotes monocyte-to-fibroblast transition in renal fibrosis","volume":"24","author":"Yang","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"2021020415161028800_gfaa062-B24","doi-asserted-by":"crossref","first-page":"3060","DOI":"10.1681\/ASN.2014070717","article-title":"JAK3\/STAT6 stimulates bone marrow-derived fibroblast activation in renal fibrosis","volume":"26","author":"Yan","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"2021020415161028800_gfaa062-B25","doi-asserted-by":"crossref","first-page":"e52415","DOI":"10.1371\/journal.pone.0052415","article-title":"Effect of interleukin 6 deficiency on renal interstitial fibrosis","volume":"7","author":"Yang","year":"2012","journal-title":"PLoS One"},{"key":"2021020415161028800_gfaa062-B26","doi-asserted-by":"crossref","first-page":"e77493","DOI":"10.1371\/journal.pone.0077493","article-title":"CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis","volume":"8","author":"Xia","year":"2013","journal-title":"PLoS One"},{"key":"2021020415161028800_gfaa062-B27","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/ki.2012.408","article-title":"Genetic deficiency of adiponectin protects against acute kidney injury","volume":"83","author":"Jin","year":"2013","journal-title":"Kidney Int"},{"key":"2021020415161028800_gfaa062-B28","doi-asserted-by":"crossref","first-page":"4964","DOI":"10.1242\/jcs.159012","article-title":"P2Y(6) receptor inhibition perturbs CCL2-evoked signalling in human monocytic and peripheral blood mononuclear cells","volume":"127","author":"Campwala","year":"2014","journal-title":"J Cell Sci"},{"key":"2021020415161028800_gfaa062-B29","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/ki.2014.287","article-title":"Origin of myofibroblasts and cellular events triggering fibrosis","volume":"87","author":"Mack","year":"2015","journal-title":"Kidney Int"},{"key":"2021020415161028800_gfaa062-B30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fphys.2016.00061","article-title":"Role of bone marrow-derived fibroblasts in renal fibrosis","volume":"7","author":"Yan","year":"2016","journal-title":"Front Physiol"},{"key":"2021020415161028800_gfaa062-B31","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1681\/ASN.2010050510","article-title":"Chemokines in renal injury","volume":"22","author":"Chung","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"2021020415161028800_gfaa062-B32","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm1284","article-title":"Blockade of PI3K\u03b3 suppresses joint inflammation and damage in mouse models of rheumatoid arthritis","volume":"11","author":"Camps","year":"2005","journal-title":"Nat Med"},{"key":"2021020415161028800_gfaa062-B33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/ndt\/gfi265","article-title":"Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases","volume":"21","author":"Ruiz-Ortega","year":"2006","journal-title":"Nephrol Dial Transplant"},{"key":"2021020415161028800_gfaa062-B34","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1160\/TH07-10-0632","article-title":"Targeting phosphoinositide 3-kinase gamma to fight inflammation and more","volume":"99","author":"Barberis","year":"2008","journal-title":"Thromb Haemost"},{"key":"2021020415161028800_gfaa062-B35","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/nm1291","article-title":"PI3K\u03b3 inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus","volume":"11","author":"Barber","year":"2005","journal-title":"Nat Med"},{"key":"2021020415161028800_gfaa062-B36","doi-asserted-by":"crossref","first-page":"C591","DOI":"10.1152\/ajpcell.00414.2012","article-title":"Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis","volume":"304","author":"Campanholle","year":"2013","journal-title":"Am J Physiol Cell Physiol"},{"key":"2021020415161028800_gfaa062-B37","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.bbalip.2014.12.006","article-title":"PI3K signalling in inflammation","volume":"1851","author":"Hawkins","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"2021020415161028800_gfaa062-B38","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/ki.2009.420","article-title":"Phosphoinositol 3-kinase-\u03b3 mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis","volume":"77","author":"Schreiber","year":"2010","journal-title":"Kidney Int"},{"key":"2021020415161028800_gfaa062-B39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/ncb1536","article-title":"Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions","volume":"9","author":"Andrew","year":"2007","journal-title":"Nat Cell Biol"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/ndt\/article-pdf\/35\/9\/1491\/36195054\/gfaa062.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/ndt\/article-pdf\/35\/9\/1491\/36195054\/gfaa062.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T12:02:44Z","timestamp":1612785764000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/35\/9\/1491\/5851543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,4]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,6,4]]},"published-print":{"date-parts":[[2020,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfaa062","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,9,1]]},"published":{"date-parts":[[2020,6,4]]}}}