title: Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats.
abstract: BACKGROUND
  Tubular atrophy is a major feature of most renal diseases and is closely associated with loss of renal function. The present study sought to investigate tubular epithelial cell apoptosis in experimental diabetic nephropathy and to explore the role of pro-apoptotic [transforming growth factor-beta (TGF-beta) and anti-apoptotic growth factors [epidermal growth factor (EGF)]. The effects of renoprotective therapy with blockade of the renin-angiotensin system (RAS) also were examined.
  
  
  METHODS
  Six-week-old female Ren-2 rats were injected with streptozotocin (STZ) and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme (ACE) inhibitor, perindopril, or the angiotensin II type 1 (AT1) receptor antagonist, valsartan, for 12 weeks.
  
  
  RESULTS
  Widespread apoptosis, identified immunohistochemically by single stranded DNA and TUNEL, was noted in the tubules of diabetic Ren-2 rats. These changes were associated with a 50% decrease in EGF expression and a twofold increase in TGF-beta1 mRNA. Treatment of diabetic Ren-2 rats with either valsartan (20 mg/kg/day) or perindopril (6 mg/kg/day) reduced apoptosis to control levels in association with supranormal levels of EGF mRNA (P < 0.01) and a reduction in TGF-beta1 gene expression (P < 0.05) to that of control rats.
  
  
  CONCLUSIONS
  Tubular apoptosis is a prominent feature of diabetic Ren-2 rats that is attenuated by blockade of the RAS in association with modulation of pro- and anti-apoptotic growth factor expression.
authors.affiliation: Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia. dkelly@medstv.unimelb.edu.au
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Mary
authors.initials: M
authors.lastname: Tolcos
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001284:Atrophy; D001345:Autoradiography; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology* / Q000503:physiopathology*; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology; D009395:Nephritis, Interstitial / Q000473:pathology / Q000503:physiopathology; D020913:Perindopril / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D012333:RNA, Messenger; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D000068756:Valsartan; D014633:Valine; D020913:Perindopril