title: Tight blood glycaemic and blood pressure control in experimental diabetic nephropathy reduces extracellular matrix production without regression of fibrosis.
abstract: OBJECTIVE
  Regression of albuminuria and renal fibrosis occurs in patients with diabetic nephropathy (DN) 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.
  
  
  METHODS
  Diabetes was induced with streptozotocin in Cyp1a1mRen2 rats and hypertension was generated by inducing renin transgene expression with dietary indole-3-carbinol (I-3-C) for 28 weeks. At this point an 'injury cohort' was culled, while in a 'reversal cohort' glycaemia was tightly controlled using insulin implants and blood pressure normalized by withdrawing dietary I-3-C for a further 8 weeks. Pathways activated during and following reversal of diabetes and hypertension were assessed by microarray profiling.
  
  
  RESULTS
  Tight control of blood glucose and blood pressure reduced albuminuria and renal hypertrophy, but had no impact on renal fibrosis. 85 genes were up-regulated specifically during the injury phase, including genes encoding multiple myofibroblast and extracellular matrix (ECM) proteins. Conversely, 314 genes remained persistently elevated during reversal including genes linked to innate/adaptive immunity, phagocytosis, lysosomal processing and degradative metalloproteinases (MMPs). Despite increased MMP gene expression, MMP activity was suppressed during both injury and reversal, in association with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Physical separation of the TIMP-1/MMP complexes during zymography of tissue homogenate restored MMP activity.
  
  
  CONCLUSIONS
  Normalization of blood glucose and pressure ameliorates albuminuria and inhibits excess ECM production, however persistent TIMP-1 expression hinders attempts at ECM remodelling. Therapies which counteract the action of TIMPs may accelerate scar resolution.
authors.affiliation: Centre for Cardiovascular Science, British Heart Foundation/University of Edinburgh, Edinburgh, UK.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
authors.forename: Boris
authors.initials: B
authors.lastname: Betz
authors.forename: Tara A
authors.initials: TA
authors.lastname: Sheldrake
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Manning
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
authors.forename: Abigail
authors.initials: A
authors.lastname: Dobyns
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles; D007328:Insulin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; C473112:Ren2 protein, mouse; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin
keywords: diabetic nephropathy; fibrosis; hyperglycaemia; hypertension; regression