title: Glomerulopathy in the KK.Cg-A(y) /J mouse reflects the pathology of diabetic nephropathy.
abstract: The KK.Cg-A (y) /J (KK-A (y) ) mouse strain is a previously described model of type 2 diabetes with renal impairment. In the present study, female KK-A (y) mice received an elevated fat content diet (24% of calories), and a cohort was uninephrectomized (Unx) to drive renal disease severity. Compared to KK-a/a controls, 26-week-old KK-A (y) mice had elevated HbA1c, insulin, leptin, triglycerides, and cholesterol, and Unx further elevated these markers of metabolic dysregulation. Unx KK-A (y) 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 TGF β 1) and inflammatory (IL-6, CD68) genes were markedly upregulated in Unx KK-A (y) mice, while podocyte markers (nephrin and podocin) were significantly decreased. These data suggest podocyte injury developing into glomerulopathy in KK-A (y) mice. The addition of uninephrectomy enhances renal injury in this model, resulting in a disease which more closely resembles human diabetic nephropathy.
authors.affiliation: Tissue Protection and Repair, Genzyme, A Sanofi Company, 49 New York Ave., Framingham, MA 01701, USA. stephen.obrien@genzyme.com
authors.forename: Stephen P
authors.initials: SP
authors.lastname: O'Brien
authors.forename: Mandy
authors.initials: M
authors.lastname: Smith
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Lucy
authors.initials: L
authors.lastname: Phillips
authors.forename: William
authors.initials: W
authors.lastname: Weber
authors.forename: John
authors.initials: J
authors.lastname: Lydon
authors.forename: Colleen
authors.initials: C
authors.lastname: Maloney
authors.forename: Steven
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Cynthia
authors.initials: C
authors.lastname: Arbeeny
authors.forename: Stefan
authors.initials: S
authors.lastname: Wawersik
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D007678:Kidney Glomerulus / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D050199:Podocytes / Q000473:pathology*