Hypertension associated renal failure in the fawn-hooded rat is the result of a genetic predisposition

Secondary complications, such as, end-stage renal disease (ESRD), heart disease and stroke are the primary causes of morbidity and mortality for hypertensive patients. Why certain patients develop one of more of these complications and others do not, despite similar levels of blood pressure and therapeutic intervention, is not known. Freedman et al. (1) suggest that ESRD has a genetic component in African-Americans. We investigated the genetic basis of hypertension associated renal failure using the fawn-hooded hypertensive rat (FHH/EUR), which is a genetic model of hypertension which develops early and chronic renal failure. To test if genetic factors contributed to the development of hypertension. 126 male backcross (FHHxACI)FHH progeny were genotyped with 130 genetic markers. We used MAPMAKER/QTL software to search for genes responsible for systolic blood pressure (SBP) and several indices of renal impairment: proteinuria, plasma creatinine, plasma albumin and a macroscopic estimate of renal damage. We located 3 genes that appear to play a role in the development of hypertension and renal impairment in this model. The Rf-1 gene accounts for nearly 50% of the genetic variance in proteinuria, but does not co-segregate with SBP. The roles of the other two genes are less clear because of their close proximity to one another. However, theBpfh-1 gene appears to be primarily responsible for the increase in SBP, accounting of 16% of the total variance. The Rf-2 gene appears to be a second independent gene involved the development of renal impairment, but only accounts for a small portion of the genetic variance in proteinuria. These data demonstrate an independent genetic predisposition for renal failure exists for the FHH, and demonstrates that molecular genetics can be used to dissect the causes of disease complications.