Pathophysiology and treatment of chronic kidney disease in rat models

Diwan, Vishal (2013). Pathophysiology and treatment of chronic kidney disease in rat models PhD Thesis, School of Biomedical Sciences, The University of Queensland.

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Author Diwan, Vishal
Thesis Title Pathophysiology and treatment of chronic kidney disease in rat models
Formatted title
School, Centre or Institute School of Biomedical Sciences
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Conrad Sernia
Brown, Lindsay C.
Gobe, Glenda C.
Total pages 247
Total colour pages 20
Total black and white pages 227
Language eng
Subjects 110312 Nephrology and Urology
110201 Cardiology (incl. Cardiovascular Diseases)
111501 Basic Pharmacology
Formatted abstract
This thesis is submitted using publications, or unsubmitted manuscripts, and supplemented with extra non-published comment from me.

Metabolic syndrome is characterised by abdominal obesity, dyslipidaemia, hypertension and hyperglycaemia and the prevalence of the disease is increasing. We require an animal model that mimics the human disease state to develop adequate therapies for metabolic syndrome. Studies in this thesis established a rat model characterising metabolic, cardiovascular, hepatic, renal and pancreatic changes in male Wistar Albino rats (8–9 weeks old) fed on a high-carbohydrate, high-fat (HCHF) diet for 16 weeks including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a corn starch diet. At 16 weeks, rats had abdominal obesity, impaired glucose tolerance, dyslipidaemia, hyperinsulinaemia, increased systolic blood pressure, endothelial dysfunction together with inflammation, fibrosis, hypertrophy and increased stiffness in the left ventricle of the heart [1]. The rats also showed structural changes with decline in liver function. However, HCHF diet-fed rats showed only minimal structural changes to the kidney without functional decline at 16 weeks.

Studies in this thesis have also evaluated the potential of piperine, a component of black pepper, and natural honey as potential therapies for metabolic syndrome. Piperine in food for last 8 weeks of a HCHF diet reversed the metabolic changes occurring because of HCHF diet. However, honey worsened most of the metabolic changes in HCHF diet-fed rats.

Chronic kidney disease (CKD) is characterised by decreased glomerular filtration rate with structural changes and persistent functional decline for more than 3 months. Cardiovascular diseases are accelerated in CKD and contribute in increased mortality rate, thus, are therefore important. Further, CKD-related cardiovascular complications are major problems worldwide. Current animal models to study human CKD have drawbacks while cardiovascular complications have not been characterised for most of the models. Chronic dietary supplementation with 0.75% adenine has been proposed [2] as an appropriate rat model of CKD; however this dose causes rapid and acute effects such as increases in plasma concentrations of blood urea nitrogen and creatinine, unlike the progressive development of CKD in humans. Moreover, cardiovascular complications have not been characterised in this model. This thesis compared the changes in kidney and cardiovascular structure and function with different dosages of adenine. The study suggests that 0.25% adenine in powdered food for 16 weeks best mimics the development of human CKD showing most of the reported structural, functional and molecular changes in kidney along with structural and functional changes in heart. This study also elucidated the possible mechanisms suggesting uric acid as key mediator behind the pathophysiological changes in 0.25% adenine-induced CKD and related cardiovascular disease. Allopurinol, a uric acid lowering agent, reversed the structural, functional and molecular changes in kidneys with structural and functional changes in hearts of adenine-fed rats. However, adenine supplementation for 16 weeks did not show abdominal obesity and glucose intolerance, being important symptoms of human metabolic syndrome.

Models such as a fructose-rich diet or high fat diet can induce few symptoms of metabolic syndrome and demonstrate kidney damage but we still need more reliable models demonstrating most of the symptoms of metabolic syndrome including kidney damage. Moreover, there is strong evidence demonstrating obesity as a risk factor for the development of CKD. Hence, the studies in this thesis evaluated the combination of HCHF and adenine diets to induce metabolic and kidney changes. Combination of HCHF diet and a lower concentration (0.075%) of adenine showed distinct structural changes in kidney along with the pathology of human metabolic syndrome demonstrating a model to study metabolic syndrome with kidney disease.

Effects of gender differences in adenine-induced CKD and cardiovascular diseases have not been characterised. Another study in this thesis demonstrated that female rats fed with 0.25% adenine showed very few functional changes in the kidney demonstrating a protective effect of female hormones against the progression of CKD. However, these female rats showed renal fibrosis, tubular atrophy and increased inflammation together with increased expression of tumour necrosis factor-α, haemeoxygenase-1and transforming growth factor-β in kidneys at 16 weeks. This study also evaluated the cardiovascular disease progression in female rats fed 0.25% adenine showing increased blood pressure and ventricular stiffness with eccentric pattern of hypertrophy. A possible mechanism for cardiac hypertrophy in both male and female hearts was demonstrated as increased expression of estrogen receptor-α and phosphorylated extracellular regulated signal kinase-1/2 (ERK-1/2) suggesting a role the ERK pathway in the development of hypertrophy in both genders.

Nod-like receptor protein-3 (NLRP-3) is activated by uric acid and the link between uric acid and NLRP-3 in CKD and cardiovascular disease has not been elucidated. One of the studies in this thesis demonstrates that supplementation with glibenclamide, an NLRP-3 inhibitor, improved structure and function of kidneys in adenine-fed rats. Glibenclamide also decreased expression of NLRP3 in kidneys of adenine-fed rats without altering plasma uric acid concentrations showing involvement of NLRP3 in pathogenesis of adenine-induced CKD and glibenclamide as a potential treatment for non-diabetic kidney disease. Further, this thesis also evaluated supplementation of the natural compound rutin as a potential treatment for CKD and demonstrated improvement in function with decrease in oxidative stress and inflammation in adenine-fed rat kidneys.

1. S.K. Panchal, H. Poudyal, A. Iyer, R. Nazer, M.A. Alam, V. Diwan, K. Kauter, C. Sernia, F. Campbell, L. Ward, G. Gobe, A. Fenning, and L. Brown. High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. Journal of cardiovascular pharmacology. 57:611-624 (2011).
2. T. Yokozawa, P.D. Zheng, H. Oura, and F. Koizumi. Animal model of adenine-induced chronic renal failure in rats. Nephron. 44:230-234 (1986).
Keyword Obesity
Metabolic syndrome
Insulin resistance
Cardiovascular disease
Type II diabetes
Chronic kidney disease

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Created: Tue, 01 Oct 2013, 18:58:38 EST by Vishal Diwan on behalf of Scholarly Communication and Digitisation Service