Hypertension is a major risk factor for stroke, heart disease and renal failure; however, it is not known why some patients with hypertension develop target organ damage whereas others do not. Studies in humans and in animals suggest that individuals can differ substantially in their susceptibility to hypertension-induced target organ damage, despite being exposed to similar levels of blood pressure. Although a number of environmental factors can enhance susceptibility to hypertension-induced target organ damage, there is evidence that genetic factors contribute to individual variation in susceptibility to the adverse effects of hypertension on the development and progression of target organ damage, including renal disease. The proposed studies will harness the separate expertise of three laboratories in a consortium-like environment and use state-of-the-art techniques in molecular genetics and renal transplantation combined with rigorous high-fidelity phenotyping of blood pressure and histological renal damage profiles to investigate mechanisms that influence susceptibility to hypertension-induced renal disease. Specifically, the investigators have devised novel experimental models derived from the spontaneously hypertensive rat and normotensive Brown Norway rat that enable them to study susceptibility to hypertension-induced damage in genetically different yet histocompatible kidneys that are simultaneously exposed to the same level of blood pressure and metabolic environment within the same host. In one such model, the right kidney is genetically identical to the left kidney except for a single chromosome region. Thus, any differences in susceptibility of these two kidneys to hypertension-induced damage can be definitively traced to the differential segment of that single chromosome. The applicants have also devised models in which genes are segregating inside the kidney but not outside the kidney, thereby enabling them to map quantitative trait loci that influence susceptibility to hypertension-induced renal damage by way of expression inside the kidney. In summary, through the combined use of advanced physiologic and genetic techniques in novel experimental models, the current studies will investigate primary mechanisms that contribute to inherited variation in susceptibility to hypertension-induced target organ damage.
