The number of patients with
hypertension-associated
end-stage renal failure (ESRF) continues to increase despite improved
antihypertensive management and early detection programs. Variation for the development of renal complications in
hypertension may reflect independent
genetic susceptibility to ESRF. The genetically hypertensive fawn-hooded rat is characterized by the early presence of
systolic hypertension, glomerular
hypertension, progressive
proteinuria (UPV), and
focal glomerulosclerosis (FGS), resulting in premature death as a result of
renal failure. In the present study, the genetic basis of
hypertension-associated ESRF in an F2 intercross consisting of 337 animals, in which systolic BP, UPV,
albuminuria, and FGS, were studied at 8 wk after a unilateral
nephrectomy performed at 5 to 6 wk of age. A total genome scan, consisting of 418 markers, was used to identify regions that contribute to the pathogenesis of UPV and FGS. Linkage analysis revealed five loci involved in the development of renal impairment. Of these five, two (Rf-1, Rf-2) had been identified previously. There seems to be strong interactive effects between the various loci and their impact on UPV and the other parameters of renal impairment, as well as an interaction with BP. In particular, Rf-1 seems to play a major role in determining the severity of the disease. This study is the first to report the interaction of more than two loci to produce progressive
renal failure, suggesting that the genetic dissection of
renal failure in humans will require understanding of how multiple genes interact with each other and BP to produce ESRF.