Adenine-induced chronic kidney and cardiovascular damage in rats

Diwan, Vishal and Mistry, Anand and Gobe, Glenda and Brown, Lindsay (2013) Adenine-induced chronic kidney and cardiovascular damage in rats. Journal of Pharmacological and Toxicological Methods , 68 (2). pp. 197-207. ISSN 1056-8719

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 16 weeks. 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 8 weeks only) was administered to determine the role of uric acid.
Results: 0.25% adenine diet induced characteristics of human chronic kidney disease at 16. weeks including increased BUN (0.25% adenine 56.5. ±. 5.4*; control 6.2. ±. 0.6. mmol/L; *. = p. <. 0.05) and plasma creatinine (0.25% adenine 268. ±. 23*; control 41.9. ±. 2.8. μg/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. Conclusion: 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.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: © 2013 Elsevier Inc. Published version deposited in accordance with the copyright policy of the publisher.
Faculty / Department / School: Historic - Faculty of Health, Engineering and Sciences - School of Health, Nursing and Midwifery
Date Deposited: 15 Aug 2013 06:05
Last Modified: 15 Jul 2014 00:30
Uncontrolled Keywords: adenine; allopurinol; cardiovascular disease; chronic kidney disease; rats; uric acid
Fields of Research : 11 Medical and Health Sciences > 1103 Clinical Sciences > 110312 Nephrology and Urology
11 Medical and Health Sciences > 1111 Nutrition and Dietetics > 111103 Nutritional Physiology
06 Biological Sciences > 0608 Zoology > 060802 Animal Cell and Molecular Biology
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970106 Expanding Knowledge in the Biological Sciences
Identification Number or DOI: 10.1016/j.vascn.2013.05.006
URI: http://eprints.usq.edu.au/id/eprint/23908

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