Synergistic QTL interactions between Rf-1 and Rf-3 increase renal damage susceptibility in double congenic rats.
The FHH (fawn-hooded hypertensive) rat is a model of hypertension-associated chronic kidney damage. Five interacting quantitative trait loci (QTLs), named Rf-1-Rf-5, determine the high renal susceptibility. The aim of the present study was to investigate a possible interaction between Rf-1 and Rf-3. Differences in renal susceptibility between ACI (August x Copenhagen Irish) controls, Rf-1A and Rf-3 single congenics, and Rf-1A+3 double congenic rats were assessed using four different treatments: two-kidney control (2K), 2K plus N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (2K+L-NAME), unilateral nephrectomy (UNX), and UNX plus L-NAME-induced hypertension (UNX+L-NAME). Proteinuria (UPV) and systolic blood pressure (SBP) were assessed after 6, 12, and 18 weeks, while the incidence of glomerulosclerosis (%FGS) was determined at the end of the experiment. In a separate experiment, renal autoregulation was assessed in 13-15-week old 2K rats of all four strains. Compared to ACI rats, small increases in renal susceptibility were found in Rf-1A and Rf-3 single congenics following 2K+L-NAME, UNX, and UNX+L-NAME treatments. However, in the Rf-1A+3 double congenics, a major increase in renal susceptibility was found with all four treatments. Both Rf-1A and Rf-1A+3 congenic rats had an impaired renal autoregulation. In contrast, the Rf-3 had a normal autoregulation, similar to that of the ACI rat. These findings indicate that Rf-1 and Rf-3 alone slightly increase the susceptibility to the development of renal damage. However, a synergistic interaction between these two QTLs markedly enhances renal susceptibility. In contrast to the Rf-1 region, the Rf-3 region does not carry genes influencing renal autoregulation.
Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.
S J
SJ
Van Dijk
P A C
PA
Specht
J
J
Lazar
H J
HJ
Jacob
A P
AP
Provoost
D000284:Administration, Oral; D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005500:Follow-Up Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D016678:Genome; D006706:Homeostasis / Q000235:genetics*; D006720:Homozygote; D006977:Hypertension, Renal / Q000209:etiology / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009392:Nephrectomy; D011507:Proteinuria / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D011912:Rats, Inbred ACI; D012079:Renal Circulation / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors
D004791:Enzyme Inhibitors; D005819:Genetic Markers; D019331:NG-Nitroarginine Methyl Ester