title: Renal cellular hypoxia in adenine-induced chronic kidney disease.
abstract: We determined whether adenine-induced chronic kidney disease (CKD) in rats is associated with renal tissue hypoxia. Adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats, daily by oral gavage, over a 15-day period. Renal function was assessed before, and 7 and 14 days after, adenine treatment commenced, by collection of a 24-hour urine sample and a blood sample from the tail vein. On day 15, arterial pressure was measured in conscious rats via the tail artery. Renal tissue hypoxia was then assessed by pimonidazole adduct immunohistochemistry and fibrosis was assessed by staining tissue with picrosirius red and Masson's trichrome. CKD was evident within 7 days of commencing adenine treatment, as demonstrated by increased urinary albumin to creatinine ratio (30 ± 12-fold). By day 14 of adenine treatment plasma creatinine concentration was more than 7-fold greater, and plasma urea more than 5-fold greater, than their baseline levels. On day 15, adenine-treated rats had slightly elevated mean arterial pressure (8 mmHg), anaemia and renomegaly. Kidneys of adenine-treated rats were characterised by the presence of tubular casts, dilated tubules, expansion of the interstitial space, accumulation of collagen, and tubulointerstitial hypoxia. Pimonidazole staining (hypoxia) co-localised with fibrosis and was present in both patent and occluded tubules. We conclude that renal tissue hypoxia develops rapidly in adenine-induced CKD. This model, therefore, should prove useful for examination of the temporal and spatial relationships between tubulointerstitial hypoxia and the development of CKD, and thus the testing of the 'chronic hypoxia hypothesis'.
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Debra
authors.initials: D
authors.lastname: Fong
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Md Mahbub
authors.initials: MM
authors.lastname: Ullah
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Jaswini G
authors.initials: JG
authors.lastname: Lal
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Amany
authors.initials: A
authors.lastname: Abdelkader
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Connie P C
authors.initials: CP
authors.lastname: Ow
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Lucinda M
authors.initials: LM
authors.lastname: Hilliard
authors.affiliation: Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.affiliation: Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Melbourne, Vic., Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Melbourne, Vic., Australia.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
mesh_terms: D000225:Adenine / Q000633:toxicity*; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000139:chemically induced / Q000652:urine*
chemical_list: D000225:Adenine
keywords: fibrosis; hypoxia; pimonidazole