Nephropathy in diabetic db/db mice is accelerated by high protein diet and improved by the SGLT2 inhibitor dapagliflozin

Abstract

The widely used db/db mouse as a model of diabetic nephropathy (DN) only mimics the early changes in human DN with a slow disease progression. Since high protein diet (HPD) has been reported to affect progression of nephropathy in both humans and mice, we investigated whether HPD could accelerate nephropathy in db/db mice. Diabetic (C57BLKS-Leprdb/db) and non-diabetic (C57BLKS-Leprdb/+) mice were fed either HPD (60 kcal% protein) or control diet (22 kcal% protein), from 7 to 22 weeks of age. In db/db mice, HPD was found to significantly increase all measured readouts of renal injury including albuminuria, renal hypertrophy, mesangial expansion and expression of a panel of DN related markers, including KIM-1, Ki67 and Collagen III, which increased on both gene and protein levels. Furthermore, HPD activated the Renin-angiotensin system significantly and increased hyperfiltration, measured as reduced plasma Cystatin C. Usefulness of the HPD db/db mouse as a model for faster drug efficacy studies was investigated in a 5-week treatment study with the SGLT2 inhibitor, dapagliflozin. Expectedly, dapagliflozin normalised blood glucose levels and improved glucose intolerance in both HPD and control diet mice. Only HPD db/db mice, not the control diet db/db mice, showed clear hyperfiltration that was significantly reduced with dapagliflozin treatment at both 2 and 4 weeks of treatment.In conclusion, these studies confirm that HPD can significantly accelerate progression of nephropathy in db/db mice, and that this model could be useful for rapid evaluation of drug targets with potential to ameliorate features of DN, especially glomerular hyperfiltration.