Why some patients with hypertension develop end stage renal disease (ESRD) and other patients with similar levels of blood pressure do not, is poorly understood. In addition, the number of patients with hypertension-associated ESRD continues to increase despite improved antihypertensive management and early detection programs. We have been studying the relationship between hypertension and ESRD using the genetically hypertensive fawn-hooded rat model (FHH/EUR). The FHH is characterized by the early presence of systemic hypertension, glomerular hypertension, progressive proteinuria and focal glomerulosclerosis, resulting in premature death due to renal failure. Treating FHH rats with an ACE inhibitor, reduces blood pressure and proteinuria, pointing to an important role for blood pressure in the pathogenesis of renal failure in this model. The interaction between hypertension and renal failure is studied using two approaches: classic physiological characterization and molecular genetics. A gene accounting for 26% of the genetic variance in systolic blood pressure was mapped to chromosome 1. This gene appears to have minimal impact on proteinuria and therefore, renal failure. However, we did locate two other genes on chromosome 1, renal failure 1 (Rf-1), and renal failure 2 (Rf-2) that together are responsible for 46% of the genetic variance in proteinuria. Importantly, Rf-l failed to account for any of the variance in blood pressure--demonstrating a genetic predisposition to renal failure in the FHH. Accordingly, we propose three specific aims: 1. Identify the Human Homologues of the Rat Rf-1 and Rf-2 genes. Providing the IRPG1 group the opportunity to determine whether the rat homologues play a role in human ESRD. 2. Clone and Identify Rf-1. Since ESRD is a multifactorial disease (polygenic with environmental interaction), the probability of cloning the gene responsible for ESRD initially in humans is remote. We will construct a congenic rat that canoes only Rf-1 thereby, reducing the model to a single gene enabling us to use standard well-studied methodologies for positional cloning. 3. Study the Interaction between Blood Pressure and the Rf-1 Gene. Continued physiological characterization of this model is essential now that we understand that the FHH has a genetic predisposition for renal failure. With the discovery of Rf-1, we will have the opportunity to study the effect of blood pressure on renal failure in our FHH and congenic models. These studies provide our best hopes of understanding the etiology of hypertension-associated ESRD.
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