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High Protein Diet Accelerates Diabetes and Kidney Disease in the BTBRob/ob Mouse.

There is a need for improved animal models that better translate to human kidney disease to predict outcome of pharmacological effects in the patient. The diabetic BTBRob/ob mouse model mimics key features of early diabetic nephropathy in humans, but with chronic injury limited to glomeruli. To explore if we could induce an accelerated and more advanced disease phenotype that closer translates to human disease, we challenged BTBRob/ob mice with a high protein diet (HPD, 30%) and followed the progression of metabolic and renal changes up to 20 weeks of age. Animals on HPD showed enhanced metabolic derangements, evidenced by further increased levels of glucose, HbA1C, cholesterol and alanine aminotransferase. The urinary albumin creatinine ratio (UACR) was markedly increased with a 53-fold change compared with lean controls, whereas BTBRob/ob on standard diet only presented an 8-fold change. HPD resulted in more advanced mesangial expansion already at 14 weeks of age as compared with BTBRob/ob mice on standard diet, and also aggravated glomerular pathology as well as interstitial fibrosis. Gene expression analysis revealed that HPD triggered expression of markers of fibrosis and inflammation in kidney and increased oxidative stress markers in urine. This study showed that HPD significantly aggravated renal injury in BTBRob/ob by further advancing albuminuria, glomerular and tubulointerstitial pathology by 20 weeks age. This mouse model offers closer translation to humans and enables exploration of new end-points for pharmacological efficacy studies that also holds promise to shorten study length.