title: Adenine-induced chronic kidney and cardiovascular damage in rats.
abstract: BACKGROUND
  The incidence of human chronic kidney failure with associated cardiovascular disease is increasing. Kidney damage can be induced in rats by chronic dietary adenine intake. We have used this intervention to investigate the development of concurrent kidney and cardiovascular injury.
  
  
  METHODS
  Dose-ranging studies were undertaken on male Wistar rats by feeding with adenine (0.075%, 0.25%, 0.5% or 0.75%) for up to 16weeks. 0.075% adenine produced minimal changes while 0.5% or 0.75% adenine produced marked kidney damage; 0.25% adenine was chosen for further studies since it produced moderate kidney and cardiovascular damage. In rats fed 0.25% adenine, renal function (blood urea nitrogen (BUN), plasma creatinine, and their clearances; plasma uric acid; proteinuria); renal structure (collagen, apoptosis, inflammation, glomerulopathy); and protein expression of markers for oxidative stress (HO-1), fibrosis (TGF-β, α-SMA) and inflammation (TNF-α, NF-κB p52, NF-κB p50, PLA2 and ED1) were measured, along with cardiovascular parameters (blood pressure, left ventricular stiffness, vascular responses). Allopurinol (25mg/kg/day, final 8weeks only) was administered to determine the role of uric acid.
  
  
  RESULTS
  0.25% adenine diet induced characteristics of human chronic kidney disease at 16weeks including increased BUN (0.25% adenine 56.5±5.4*; control 6.2±0.6mmol/L; *=p<0.05) and plasma creatinine (0.25% adenine 268±23*; control 41.9±2.8μg/L), decreased BUN and creatinine clearances; proteinuria; increased chronic inflammation as macrophage and myofibroblast infiltration, increased collagen deposition, tubular atrophy, apoptosis, and TNF-α and TGF-β expression; glomerulopathy as increased podocyte desmin expression; increased HO-1 expression; and increased plasma uric acid. Cardiovascular changes included increased ventricular fibrosis, systolic blood pressure and left ventricular stiffness, and impaired vascular responses. Allopurinol decreased plasma uric acid concentrations and reversed the adenine-induced kidney and cardiovascular changes.
  
  
  CONCLUSIONS
  Administration of 0.25% adenine to rats induced chronic kidney and cardiovascular disease. Increased uric acid production is the most likely cause since allopurinol attenuated this damage.
authors.affiliation: School of Biomedical Science, The University of Queensland, Australia; Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Australia.
authors.forename: Vishal
authors.initials: V
authors.lastname: Diwan
authors.affiliation: Department of Biological and Physical Sciences, The University of Southern Queensland, Australia.
authors.forename: Anand
authors.initials: A
authors.lastname: Mistry
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Australia.
authors.forename: Glenda
authors.initials: G
authors.lastname: Gobe
authors.affiliation: Department of Biological and Physical Sciences, The University of Southern Queensland, Australia. Electronic address: Lindsay.Brown@usq.edu.au.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000633:toxicity*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D006074:Gout Suppressants / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014527:Uric Acid / Q000097:blood*
chemical_list: D006074:Gout Suppressants; D014527:Uric Acid; D000493:Allopurinol; D000225:Adenine
keywords: Adenine; Allopurinol; Cardiovascular disease; Chronic kidney disease; Rats; Uric acid