The KK.Cg- /J (KK- ) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK- mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK- controls, 26-week-old KK- mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK- mice also exhibited elevated serum BUN and reduced glomerular filtration, indicating that reduction in renal mass leads to more severe impairment in renal function. Glomerular hypertrophy and hypercellularity, mesangial matrix expansion, podocyte effacement, and basement membrane thickening were present in both binephric and uninephrectomized cohorts. Glomerular size was increased in both groups, but podocyte density was reduced only in the Unx animals. Consistent with functional and histological evidence of increased injury, fibrotic (fibronectin 1, MMP9, and TGFβ1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK- mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK- mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy. 1. Introduction Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) and is associated with high cardiovascular risk and significant morbidity and mortality [1, 2]. Disease progression is difficult to predict, as rates of decline in glomerular filtration rate (GFR) are variable in this patient population and only one-third of diabetic patients, the majority of whom have type 2 diabetes (T2D), develop progressive renal failure. The pathogenesis of DN is mediated by a complex interplay of genetic and environmental modifiers resulting in hemodynamic and structural changes in the kidney that contribute to progressive functional loss in both the glomerulus and tubular-interstitial epithelium [3, 4]. Central to disease progression is glomerular injury, with pathological changes including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, mesangial matrix expansion, and subsequent glomerulosclerosis [3]. Podocytes are critical to the functional glomerular filtration barrier and are particularly sensitive to damage by the “diabetic milieu” of dysglycemia, dyslipidemia, hemodynamic changes, and inflammation [5, 6]. In
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