Evidence of gene-gene interactions in the genetic susceptibility to renal impairment after unilateral nephrectomy

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 compli cations in hypertension may reflect independent genetic susceptibility to E SRF. The genetically hypertensive fawn-hooded rat is characterized by the e arly presence of systolic hypertension, glomerular hypertension, progressiv e proteinuria (UPV), and focal glomerulosclerosis (FGS), resulting in prema ture 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 c ontribute to the pathogenesis of UPV and FGS, Linkage analysis revealed fiv e loci involved in the development of renal impairment. Of these five, two (Rf-1, Rf-2) had been identified previously. There seems to he strong inter active effects between the various loci and their impact on UPV and the oth er parameters of renal impairment, as well as an interaction with BP. In pa rticular, Rf-1 seems to play a major role in determining the severity of th e disease. This study is the first to report the interaction of more than t wo loci to produce progressive renal failure, suggesting that the genetic d issection of renal failure in humans will require understanding of how mult iple genes interact with each other and BP to produce ESRF.