Abstract
BackgroundThe end stage renal disease population has a 20 fold higher incidence of cardiovascular mortality compared to the overall population. The development of reno-cardiac syndrome in these patients will result in cardiovascular events to be the cause of 50% of fatalities. There is therefore a need to research improved therapeutic strategies to combat renal cardiac pathologies. Murine in vivo models contribute greatly to such research allowing for specific genetic modification and reduced miscellany, however there is currently no reliable model of reno-cardiac syndrome in the most common genetically modified mouse strain, the C57BL/6. In this study we have manipulated an established model of chronic renal disease using adenine infused diet and prolonged the course of its pathology achieving chronic renal failure and subsequent reno-cardiac syndrome in the C57BL/6 mouse.MethodsEight week-old male C57BL/ 6 mice were acclimatised for 7 days before administration of a 0.15% adenine diet or control diet for 20 weeks.Cardiac function was assessed in mice at week 20 by echocardiography. At experiment termination blood and urine samples were analysed biochemically and organ dysfunction/injury was determined using immunoblotting and immunohistochemistry.ResultsAdministration of 0.15% adenine diet caused progressive renal failure resulting in reno-cardiac syndrome. At endpoint uraemia was confirmed by blood biochemistry which in the adenine fed mice showed significant increases in serum creatinine, urea, calcium (P < 0.0001) potassium (P < 0.05), and a significantly reduced glomerular filtration rate (P < 0.05). Reno-cardiac syndrome was confirmed by a significantly increased heart to body weight ratio (P < 0.0001) and echocardiography which showed significant reductions in percentage of ejection fraction, fractional shortening, fractional area change, (P < 0.0001) and an increase in left ventricular end diastolic volume (P < 0.05). Immunoblotting of kidney and heart tissue showed increased apoptosis (caspase 3) and fibrosis (fibronectin) and increases in the cardiac levels of phosphorylated Akt, and renal total Akt. Immunohistochemistry for α-SMA, collagen 1 and collagen 3 further confirmed fibrosis.ConclusionsWe present a novel regimen of adenine diet which induces both chronic kidney disease and reno-cardiac syndrome in the C57/BL6 mouse strain. The non-surgical nature of this model makes it highly reproducible compared to other models currently available.
Highlights
The end stage renal disease population has a 20 fold higher incidence of cardiovascular mortality compared to the overall population
In mice, this model is much less effective giving highly variable results [10]. This is further compounded by the fact that the C57BL/ 6 mouse strain, the preferred strain for genetic modification [11] has been shown to be resistant to developing Chronic kidney disease (CKD) by subtotal nephrectomy [12]
Two animals from each group were sacrificed at weeks 12 and 16 in order to determine the progression of uraemia (BMC Additional file 2)
Summary
The end stage renal disease population has a 20 fold higher incidence of cardiovascular mortality compared to the overall population. 50% of mortality in ESRD patients is as a result of cardiovascular events [4, 5] These factors highlight the need for the continued improvement of therapeutic strategies to combat RCS. Fibroblast activation leads to eventual cardiac hypertrophy and fibrosis [8, 9] In mice, this model is much less effective giving highly variable results [10]. This is further compounded by the fact that the C57BL/ 6 mouse strain, the preferred strain for genetic modification [11] has been shown to be resistant to developing CKD by subtotal nephrectomy [12]
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