Genetic Analysis of Renal Disease in SHR and Dahl S Rats

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DESCRIPTION (Verbatim from the application): End stage renal disease (ESRD) in humans is an important medical problem requiring the expensive treatments of dialysis and renal transplantation. Studies in humans suggest that ESRO has a complex genetic component. In order to understand the genetic causes of ESRD we propose to define the genetic components responsible for the development of the rapidly progressing renal pathology in the Dahi salt sensitive (S) rat. To do this, segregating populations derived from crossing S rats with spontaneously hypertensive rats (SHR) will be studied. The two strains are markedly different with regard to proteinuria and progression of renal disease. Young S rats have very high proteinuria and rapidly develop renal lesions; young SHR show essentially minimal proteinuria and very slow progression of renal disease in spite of their high blood pressure. Linkage analysis for the quantitative trait loci (QTL) controlling the marked difference in proteinuria between S and SHR will be performed starting at a young age and also at successive time points in an F2(SHR X S) population fed a low salt diet to minimize the development of hypertension. The QTL for blood pressure that differentiate S and SHR rats have already been defined on high salt diet as residing on rat chromosomes 3, 6, 8 and 9. The relationship of these blood pressure QTL to the QTL for progressive proteinuria/renal disease will be sought by determining the positions of the QTL for both traits in an F2(SHR X S) population fed high salt diet. One of the blood pressure QTL differentiating S and SHR is likely to be related to the marked difference in the vascular smooth muscle response between S and SHR to ionic cobalt. This is a Mendelian trait and it will be placed on the rat genetic map to determine its relationship to blood pressure and proteinuria QTL. Lastly, the development of congenic strains will be initiated for any unique QTL, especially those for proteinuria/renal disease, defined by the above genetic analysis. These congenic strains are required for later fine genetic mapping and ultimate gene identification.