Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat

Abstract

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

Quantitative Trait Loci for Glomerulosclerosis, Kidney Weight and Body Weight in the Focal Glomerulosclerosis Mouse Model

“…Based on the histological features of the FGS/Kist kidney, we here detected two QTLs for GSI, Gsi1&2, on Chrs 8 and 10. These QTLs were not homologous to those of the above rat models [2,4,19]. Thus, the FGS/Kist mouse may play an important role as a new source of QTLs to further FGS study.…”

“…As the phenotypic effects of one locus on different traits, e.g. proteinuria and renal sclerosis score, are reported in the fawn-hooded hypertensive rat [2], Ptnu1 and Gsi1 may be potentially the same locus with pleiotropic effects on proteinuria and glomerulosclerosis.…”

“…In the fawn-hooded hypertensive rat, which develops severe renal damage with mild hypertension, a QTL for the degree of renal damage has been reported on Chr 1 [2], and a high susceptibility to renal damage has been observed in SHR rats carrying a segment of Chr 1 from Brown Norway rats [12]. More recently three QTLs explained increased urinary albumin excretion in the Munich Wistar Fromter rat, a model of chronic nephropathy [19].…”

“…Multiple studies using rat models have identified many quantitative trait loci (QTLs) associated with renal related parameters such as urinary proteinuria, renal index score etc. [2,4,15,19]. However, to date, little is known about the genetic basis for the predisposition to renal complications.…”

Improvement in treatment of hypertension has not reduced incidence of end-stage renal disease

“…Brown et al 56 has identified a gene that predisposes to hypertensive renal injury and has no apparent effect on blood pressure. It is possible that this gene or other genes are linked with the failure of the afferent arteriole to antoregulate and therefore lead to a high glomerular pressure and hyperfiltration.…”