Abstract: Diabetic nephropathy (DN) is a disease of monumental proportions both in terms of human suffering and public health expenditures. Approximately six percent of the U.S. population has diabetes mellitus, 10-20% of which develop DN, ultimately progressing to end stage renal disease (ESRD). The factors contributing to DN remain obscure. While hyperglycemia is a necessary trigger, alone, it is insufficient to cause DN. Sibling studies suggest a strong genetic component, however defining the specific genetic loci contributing to DN in man has been confounded by the heterogeneous causes of diabetes, and by the diversity of human genetic background. In contrast, the wide availability of genetically homogenous mouse strains, coupled with advances in transgenic technology, make mice uniquely amenable to dissection of the molecular mechanisms of disease. As in man, most mice do not develop diabetic nephropathy, and the array of genes that confer susceptibility to DN to this minority, have not been characterized. This proposal is to generate a robust murine model of DN that closely parallels the human disease; that is genetically defined; and can be easily transferred between mouse strains. To achieve these goals we propose to identify specific genes that convert the "nephropathy resistant" C57BL/6 strain to one that develops DN. We will take two approaches. The first will use a "candidate gene" approach. In man, patients susceptible to DN exhibit worse hypertension and dyslipidemia than those resistant to nephropathy. Treatment of these conditions slows the progression of nephropathy. Polymorphisms in Angiotensinogen (Atg) eNOS and ApoE alleles have been described in susceptible patients. The first specific aim will examine the effect of superimposing the hypertensive human Atg transgenic, eNOS-/- or hyperlipidemic ApoE-/- alleles on two different models of diabetes, insulin deficient HN6 transgenic mice and insulin resistant db/db mice. The second approach will attempt to identify novel dominant modifiers that predispose to DN. Diabetic HNF6 or db/db C57BL/6 mice will be mutagenized with ethylnitrosourea (ENU) and G 1 offspring screened for DN (renal insufficiency and/or proteinuria). These studies should not only yield a well-defined mouse model of DN, but also provide important new information regarding genes that contribute to the development of DN.