Genetic locus on MWF rat chromosome 6 affects kidney damage in response to L-NAME treatment in spontaneously hypertensive rats.
A major quantitative trait locus (QTL) on rat chromosome (RNO)6 was linked to albuminuria in Munich Wistar Frömter rats (MWF). We tested whether transfer of MWF RNO6 into the background of albuminuria-resistant spontaneously hypertensive rats (SHR) induces albuminuria in consomic SHR-6(MWF) animals. Male MWF, SHR, and SHR-6(MWF) were sham operated and treated between 6 and 24 wk of age with normal water (Sham) or with water containing 20 mg/l N(G)-nitro-L-arginine methyl ester (L-NAME) or unilaterally nephrectomized (Nx). Compared with SHR albuminuria was not increased in SHR-6(MWF) in both Sham and Nx groups. All animals survived the observation period in Sham and Nx groups, while premature mortality occurred from 12-14 wk on in L-NAME-treated SHR and SHR-6(MWF) compared with MWF L-NAME animals, in which survival was not affected (P < 0.005, respectively). Subsequent further analysis of L-NAME-treated animals at 12 wk of age showed significantly increased arterial blood pressures in both SHR and SHR-6(MWF) compared with control (P < 0.05), with higher levels in SHR compared with consomics (P < 0.05). However, L-NAME-treated consomic animals demonstrated increased albuminuria compared with SHR (12.7 +/- 3.5 vs. 0.8 +/- 0.2 mg/24 h; P < 0.05) and an induction of tubulointerstitial structural injury and expression of neutrophil gelatinase-associated lipocalin mRNA (P < 0.05 vs. other strains). Our study demonstrates that isolation of the RNO6 albuminuria QTL from the MWF background and transfer into SHR fails to induce an albuminuria phenotype during normal conditions or after nephron reduction. Moreover, our data indicate that genes on RNO6 contribute to the development of L-NAME-induced renal damage in the SHR strain.
Schulz
Angela
A
Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité-Universitätsmedizin Berlin, Berlin, Germany. angela-martina.schulz@charite.de
Schütten
Sabrina
S
Schulte
Leonard
L
Kossmehl
Peter
P
Nyengaard
Jens R
JR
Vetter
Roland
R
Huber
Matthias
M
Kreutz
Reinhold
R
D000419:Albuminuria / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009392:Nephrectomy; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013997:Time Factors
D004791:Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester