Interaction between Rf-1 and Rf-4 quantitative trait loci increases susceptibility to renal damage in double congenic rats.
BACKGROUND
Five quantitative trait loci (QTLs), Rf-1 to Rf-5, were found in Fawn-Hooded hypertensive (FHH) rats influencing susceptibility to renal damage. Previously, we found that single transfer of the Rf-1 QTL from FHH rats onto the renal-resistant August x Copenhagen Irish (ACI) strain caused a small increase in renal susceptibility. To investigate the separate role of the Rf-4 QTL and its interaction with Rf-1, we generated a single congenic strain carrying Rf-4 and a double congenic carrying both Rf-1 and Rf-4.


METHODS
Differences in renal susceptibility between ACI, Rf-1A, and Rf-4 single congenics and Rf-1A+4 double congenics were assessed using four different treatments: control (two-kidney), two-kidney with l-arginine analogue N-nitro-l-arginine methyl ester (L-NAME)-induced hypertension, unilateral nephrectomy, and unilateral nephrectomy + L-NAME. In separate experiments, renal blood flow (RBF) autoregulation was compared between two-kidney ACI and congenic rats.


RESULTS
Compared to ACI, Rf-1A rats developed more renal damage, while Rf-4 rats did not. The most severe renal damage was found in the Rf-1A+4 double congenic rats. Analysis of variance (ANOVA) demonstrated a significant interaction between the Rf-1A and Rf-4 QTLs. The magnitude of the interaction varied with the type and duration of the treatment. The RBF autoregulation was impaired in Rf-1A single and Rf-1A+4 double congenics, while in Rf-4 single congenics it was similar to that of ACI controls.


CONCLUSIONS
These findings indicate that the Rf-1 QTL directly influences renal susceptibility and autoregulation. In contrast, the Rf-4 QTL shows no direct effects, but significantly increases susceptibility to renal damage via an interaction with Rf-1.
Van Dijk
Sabine J
SJ
Department of Paediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.
Specht
Patricia A C
PA
Lutz
Michelle M
MM
Lazar
Jozef
J
Jacob
Howard J
HJ
Provoost
Abraham P
AP
D000419:Albuminuria / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics; D033481:Chromosomes, Mammalian; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006720:Homozygote; D006977:Hypertension, Renal / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D040641:Quantitative Trait Loci; D051381:Rats; D011912:Rats, Inbred ACI; D012079:Renal Circulation / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D015996:Survival Rate