title: A new mouse model resembling human diabetic nephropathy: uncoupling of VEGF with eNOS as a novel pathogenic mechanism.
abstract: Diabetics develop a variety of histological abnormalities in the kidney. Early features include glomerular hypertrophy, glomerular basement membrane thickening, and mesangial expansion, whereas mesangiolysis, glomerular capillary aneurysm and nodular lesions develop in late phase. The goal of preventing diabetic nephropathy is important, but its achievement has been difficult due in part to a lack of an animal model for human diabetic nephropathy. Most animal models develop mild lesions in early phase diabetes, but not advanced lesions in late phase. Vascular endothelial growth factor (VEGF) mediates diabetic nephropathy, but its precise role remains to be determined. A complexity of VEGF function is that it is protective in nondiabetic renal diseases but is deleterious in diabetic nephropathy. Because diabetes is associated with endothelial dysfunction, we hypothesized that VEGF is deleterious in the setting of endothelial dysfunction. To test this hypothesis, we recently developed a new model of diabetic nephropathy in mice deficient in endothelial nitric oxide synthase (eNOS). Importantly, these mice developed the advanced lesions of diabetic nephropathy resembling to those in human diabetic nephropathy. In addition, these models also exhibit an uncoupling condition of VEGF with NO. In this review, we discuss our hypothesis which is that uncoupling of VEGF with NO causes advanced diabetic nephropathy.
authors.affiliation: Division of Renal Disease and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA. Takahiko.Nakagawa@uchsc.edu
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D004195:Disease Models, Animal; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III