{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:03:34Z","timestamp":1790244214557,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T00:00:00Z","timestamp":1541030400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yokohama Foundation for Advancement of Medical Science"},{"name":"Uehara Memorial Foundation grant"},{"name":"Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science"},{"name":"SENSHIN Medical Research"},{"DOI":"10.13039\/100007716","name":"Banyu Life Science Foundation International","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007716","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009666","name":"Salt Science Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009666","id-type":"DOI","asserted-by":"publisher"}]},{"name":"grant-in-aid from the Cardiovascular Research Fund, Tokyo, Japan"},{"name":"Strategic Research Project of Yokohama City University, Japan Agency for Medical Research and Development"},{"name":"Translational Research program; Strategic PRomotion for practical application of INnovative medical Technology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2018,11,1]]},"abstract":"<jats:p>Abnormal angiogenesis plays a major role in the development of early stage diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a classical proangiogenic factor that regulates abnormal glomerular angiogenesis linked to glomerular hypertrophy in the early stage of diabetic nephropathy. Leucine-rich <jats:italic>\u03b1<\/jats:italic>-2-glycoprotein-1 (LRG1) was recently reported as a novel proangiogenic factor that is expressed in endothelial cells and promotes angiogenesis by modulating the transforming growth factor-<jats:italic>\u03b2<\/jats:italic> signaling pathway. However, the pathophysiology of LRG1 in diabetic nephropathy remains largely unknown. In the present study, we investigated intrarenal expression of the novel proangiogenic factor LRG1 in diabetic<jats:italic> db\/db<\/jats:italic> mice by immunohistochemistry and a laser capture microdissection method during the development of diabetic nephropathy. We hypothesized that glomerular LRG1 expression is increased earlier than VEGF expression under conditions of pathological angiogenesis in the early stage of diabetic nephropathy. Thus, we compared glomerular expression of VEGF and LRG1 in diabetic<jats:italic> db\/db<\/jats:italic> mice at 16 and 24 weeks of age. At 16 weeks, diabetic<jats:italic> db\/db<\/jats:italic> mice exhibited glomerular hypertrophy with abnormal angiogenesis characterized by endothelial cell proliferation, which was concomitant with an increase in LRG1 expression of glomerular endothelial cells. However, glomerular VEGF expression was not increased at this early stage. At 24 weeks, the features of early diabetic nephropathy in<jats:italic> db\/db<\/jats:italic> mice had developed further, along with further enhanced glomerular LRG1 expression. At this late stage, glomerular VEGF and fibrosis-related-gene expression was also significantly increased compared with nondiabetic<jats:italic> db\/m<\/jats:italic> mice. These results suggest that LRG1 plays a pivotal role in the initial development of diabetic nephropathy by promoting abnormal angiogenesis, thereby suggesting that LRG1 is a potential preemptive therapeutic target of diabetic nephropathy.<\/jats:p>","DOI":"10.1155\/2018\/2817045","type":"journal-article","created":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T19:49:58Z","timestamp":1541101798000},"page":"1-9","source":"Crossref","is-referenced-by-count":28,"title":["Early Enhanced Leucine-Rich <i>\u03b1<\/i>-2-Glycoprotein-1 Expression in Glomerular Endothelial Cells of Type 2 Diabetic Nephropathy Model Mice"],"prefix":"10.1155","volume":"2018","author":[{"given":"Sona","family":"haku","sequence":"first","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8023-922X","authenticated-orcid":true,"given":"Hiromichi","family":"Wakui","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5136-0730","authenticated-orcid":true,"given":"Kengo","family":"Azushima","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"},{"name":"Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Haruhara","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"},{"name":"Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Kinguchi","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohji","family":"Ohki","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazushi","family":"Uneda","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1075-2372","authenticated-orcid":true,"given":"Ryu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Minegishi","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Ishigami","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0660-5372","authenticated-orcid":true,"given":"Kouichi","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.4103\/1110-9165.197379"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00266.2015"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2005.00492.x"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes."},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-6632(87)80069-7"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0119"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2012.04.004"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-002-0780-2"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1007\/BF00399925"},{"issue":"7","key":"10","first-page":"1448","volume":"12","year":"2001","journal-title":"Biomed Research International"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2001.280.4.F727"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6740"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5724069"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2012.681043"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1038\/nature12345"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.02.028"},{"issue":"4","key":"17","volume":"2","year":"2013","journal-title":"Journal of the American Heart Association"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.004488"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006120"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2014.95"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt225"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2018.01.013"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.10.035"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1038\/srep27137"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.00572"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1007\/BF00401056"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.142"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0306-2"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2010.06.006"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1743"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120055097"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64121-1"},{"key":"33","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02708-0"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/463740"}],"container-title":["BioMed Research International"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/2817045.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/2817045.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/2817045.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T19:50:11Z","timestamp":1541101811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/bmri\/2018\/2817045\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,1]]},"references-count":34,"alternative-id":["2817045","2817045"],"URL":"https:\/\/doi.org\/10.1155\/2018\/2817045","relation":{},"ISSN":["2314-6133","2314-6141"],"issn-type":[{"value":"2314-6133","type":"print"},{"value":"2314-6141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,1]]}}}