Genes That Regulate Progression of Kidney Disease and Its Cardiovascular Effects

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DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) and proteinuria are powerful risk factors for cardiovascular disease. The prevalence of hypertension, ischemic heart disease, left ventricular hypertrophy (LVH) and heart failure are disproportionately higher in patients with CKD than in the general population, even after adjustment for traditional cardiovascular risk factors. Importantly, CKD patients are more likely to die of cardiovascular disease than to develop kidney failure. Due to the magnitude and implications of CKD, in 2001, the National Institute of Diabetes, Digestive, and Kidney Disease established the Chronic Renal Insufficiency Cohort (CRIC) Study to examine risk factors for progression of CKD and cardiovascular disease among patients with CKD. Epidemiological studies suggest that there is a strong genetic component determining susceptibility for renal disease, and by inference, for its associated cardiovascular risks. We hypothesize that there are heritable factors that contribute to progression of CKD and its consequences in the cardiovascular system. Using sub-total nephrectomy in the mouse, a well-established model of CKD, we have identified 2 novel QTLs that regulate CKD-induced hypertension (Ckdbpl and Ckdbp2). We have also found an area of linkage with cardiac hypertrophy (Ckdlvhl) that is distinct from the QTLs for blood pressure. In addition, we have identified a QTL that regulate the severity of albuminuria, and this is the same locus found for the blood pressure QTL Ckdbp2. The goal of this project is to identify genes that confer susceptibility to the cardiovascular consequences chronic kidney disease. We will focus on the strongest QTLs, Ckdbp2 and Ckdlvhl for fine mapping and gene identification. The methods and techniques used for gene identification will include generation of congenic mouse strains for each locus, recombinant progeny testing to assist in fine-mapping, DMA sequence analysis to identify sequence variants, and prioritization of candidate genes using mRNA expression analysis. Identification and characterization of these susceptibility genes will increase our understanding of the molecular mechanisms underlying the progression of CKD and its cardiovascular effects, and may provide targets for therapeutic intervention.