ESRD is a major health problem in the United States, with increasing incidence. Hypertension and diabetes account for more than 67% of ESRD. These associations are not understood, but many believe there is a final common pathway for renal failure independent of inducing agent or disease. Not everyone with hypertension or diabetes develops ESRD, and we demonstrated that renal failure genes could be independent of hypertension. We have a comprehensive research program utilizing genetics, genomics, transgenics to study the interactions of hypertension, diabetes and renal disease susceptibility genes. The goal of this proposal is to identify genes responsible for susceptibility to hypertension-related ESRD, and to identify the physiological pathways involved. We propose three specific aims: 1. Validate that Rab38 is the Rf-2 gene. We recently reported Rab38 to be the Rf-2 gene. We hypothesize that the Rab38 gene has pleiotropic effects and contributes to the development of proteinuria in FHH rats. We will test this hypothesis by a) studying albumin uptake in primary cultures of proximal tubule and b) with transgenic "rescue". 2. Complete the positional cloning and validation of the Rf-1 gene and Rf-4 gene. The Rf-1 QTL isthe dominant locus for ESRD in the FHH. Importantly, this locus has a strong interaction with Rf-4. We have reduced both the Rf-1 interval to 2.5 cM and the Rf-4 interval to 0.8cM, and the entire region has been sequenced in BN rats to a nearly finished level. We will investigate each locus using sub-congenics, physiological studies and sequence comparison to identify the causal gene(s) in both loci. Causal genes will be validated by rat transgenic rescue in the FHH genome background. 3. Initiate the positional cloning of Rf-3. We have demonstrated our ability to clone genes by position. We show that Rf-3 is also in a region linked to renal disease in mouse and human as is the case for Rf-1,-2, and -4. We will use the existing double (Rf-1+3) congenic strain to generate the overlapping congenics in the Rf-3 interval. We are confident that we will either find the gene or narrow down the interval to a handful of genes when we complete the term of this grant.