{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:04:14Z","timestamp":1790024654841,"version":"4.0.1"},"reference-count":25,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T00:00:00Z","timestamp":1416268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000291","name":"Kidney Research UK","doi-asserted-by":"publisher","award":["IN5-2012"],"award-info":[{"award-number":["IN5-2012"]}],"id":[{"id":"10.13039\/501100000291","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Nephrology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"Abstract<\/jats:title>Aims<\/jats:title>Regression of albuminuria and renal fibrosis occurs in patients with diabetic nephropathy (DN<\/jats:styled-content>) following tight control of blood glucose and blood pressure, however the pathways that promote regression remain poorly understood and we wished to characterize these using a rodent model.<\/jats:p><\/jats:sec>Methods<\/jats:title>Diabetes was induced with streptozotocin in Cyp1a1mRen2<\/jats:styled-content> rats and hypertension was generated by inducing renin transgene expression with dietary indole\u20103\u2010carbinol (I<\/jats:styled-content>\u20103\u2010C<\/jats:styled-content>) for 28 weeks. At this point an \u2018injury cohort\u2019 was culled, while in a \u2018reversal cohort\u2019 glycaemia was tightly controlled using insulin implants and blood pressure normalized by withdrawing dietary I<\/jats:styled-content>\u20103\u2010C<\/jats:styled-content> for a further 8 weeks. Pathways activated during and following reversal of diabetes and hypertension were assessed by microarray profiling.<\/jats:p><\/jats:sec>Results<\/jats:title>Tight control of blood glucose and blood pressure reduced albuminuria and renal hypertrophy, but had no impact on renal fibrosis. 85 genes were up\u2010regulated specifically during the injury phase, including genes encoding multiple myofibroblast and extracellular matrix (ECM<\/jats:styled-content>) proteins. Conversely, 314 genes remained persistently elevated during reversal including genes linked to innate\/adaptive immunity, phagocytosis, lysosomal processing and degradative metalloproteinases (MMPs<\/jats:styled-content>). Despite increased MMP<\/jats:styled-content> gene expression, MMP<\/jats:styled-content> activity was suppressed during both injury and reversal, in association with up\u2010regulation of tissue inhibitor of metalloproteinase\u20101 (TIMP<\/jats:styled-content>\u20101) protein. Physical separation of the TIMP<\/jats:styled-content>\u20101\/MMP<\/jats:styled-content> complexes during zymography of tissue homogenate restored MMP<\/jats:styled-content> activity.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Normalization of blood glucose and pressure ameliorates albuminuria and inhibits excess ECM<\/jats:styled-content> production, however persistent TIMP<\/jats:styled-content>\u20101 expression hinders attempts at ECM<\/jats:styled-content> remodelling. Therapies which counteract the action of TIMPs<\/jats:styled-content> may accelerate scar resolution.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nep.12335","type":"journal-article","created":{"date-parts":[[2014,9,5]],"date-time":"2014-09-05T05:32:29Z","timestamp":1409895149000},"page":"802-813","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Tight blood glycaemic and blood pressure control in experimental diabetic nephropathy reduces extracellular matrix production without regression of fibrosis"],"prefix":"10.1111","volume":"19","author":[{"given":"Bryan R.","family":"Conway","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular Science British Heart Foundation\/University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Betz","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara A.","family":"Sheldrake","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Manning","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science British Heart Foundation\/University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald R.","family":"Dunbar","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science British Heart Foundation\/University of Edinburgh Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Illinois at Chicago Chicago Illinois 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