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Journal of Diabetes Research
Volume 2013 (2013), Article ID 498925, 13 pages
http://dx.doi.org/10.1155/2013/498925
Research Article

Glomerulopathy in the KK.Cg-Ay/J Mouse Reflects the Pathology of Diabetic Nephropathy

Tissue Protection and Repair, Genzyme, A Sanofi Company, 49 New York Ave., Framingham, MA 01701, USA

Received 23 January 2013; Accepted 15 March 2013

Academic Editor: Daisuke Koya

Copyright © 2013 Stephen P. O'Brien et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.