Characterization of the Mouse Adenine Nephropathy Model: Kidney Proteomic Profiling

Background: Most models of chronic kidney disease in mice do not show a robust inflammation/fibrosis response. In this study, we sought renal injury and function in mice fed an adenine-rich diet. Methods: Ten weeks-old C57Bl/6 mice were fed an adenine-rich diet (0.15%) for 6 weeks. Noninvasive renal oxygen content, renal stiffness and transcutaneous glomerular filtration rate (GFR) were determined at the end of the experiment. Tubular integrity was measured using the furosemide test and correlated with histology and expression of tubular injury biomarkers. The remaining kidneys were harvested, and proteomics analysis was performed on the cortical fraction. Results: In adenine-fed mice, we observed a progressive reduction in GFR, which reached ~30% of the initial value at 6 weeks. Renal oxygenation was reduced, and renal stiffness was increased in the adenine-fed mice. Histology showed a significant increase in tubular degeneration, inflammation and fibrosis, the latter correlating well with renal stiffness. Adenine-fed mice had an impaired response to furosemide, suggesting a disruption of tubular integrity. Nephron segment-specific injury marker analysis showed that the proximal tubules, cortical thick limb of the loop of Henle and distal tubules were injured in this model. Proteomic analysis showed a massive increase in pathways associated with extracellular matrix expansion, inflammation and complement cascade, while pathways associated with TCA cycle and respiration, transport activity, amino acid metabolism and peroxisomal lipid metabolism were downregulated. Conclusion: An adenine-rich diet causes a progressive loss of renal function that is associated with a significant increase in tubular injury, fibrosis and inflammation, and a reduction in tubular transport activity and energy metabolism. Therefore, adenine causes chronic renal failure in mice, which manifests as progressive renal insufficiency and metabolic abnormalities that are similar to those seen in patients with chronic kidney disease.