Genetic locus on MWF rat chromosome 6 affects kidney damage in response tol-NAME treatment in spontaneously hypertensive rats

Abstract

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.

Induction of albuminuria and kidney damage in SHR by transfer of chromosome 8 from Munich Wistar Frömter rats

“…Time-course analysis for urinary albumin excretion (UAE) at 12, 18, and 24 wk of age was performed in accordance with our previous studies (21,23). SBP was determined by a tail-cuff method in awake animals at 24 wk of age on a computer-assisted oscillatory detection device (TSE, Bad Homburg, Germany) (12).…”

“…These investigations were done in single-and double-consomic rat strains in which single replacement of either RNO6 [MWF-Chr 6 SHR /Rkb (RGD:1641831)] or RNO8 [MWF-Chr 8 SHR /Rkb (RGD: 2312609), referred to as MWF-8 SHR in this publication] or double replacement of both chromosomes (MWF-Chr 6 SHR Chr 8 SHR /Rkb) was achieved by introgressing these chromosomes from albuminuria-resistant spontaneously hypertensive rats (SHR/FubRkb, referred to as SHR in this publication) into the sensitive isogenic background of MWF (18,20,23). In contrast to this common protocol in which a QTL is replaced in the disease strain by alleles of the resistant strain (15), here in a reciprocal approach we generated a new consomic SHR-8 MWF strain by transferring RNO8 from MWF into the albuminuria-resistant SHR strain (21). Thus, we tested whether QTL on RNO8 are capable of inducing the albuminuria phenotype in SHR rats after isolation from the permissive disease background in MWF.…”

Elimination of Severe Albuminuria in Aging Hypertensive Rats by Exchange of 2 Chromosomes in Double-Consomic Rats

“…14 Figure 4A). Interestingly, double-consomic animals showed UAE levels that were even lower than those observed in albuminuria-resistant SHRs (0.8Ϯ0.1 versus 2.3Ϯ0.3 mg/24 hours; PϽ0.0001; Figure 4A).…”

Mapping genetic determinants of kidney damage in rat models

“…144 In contrast, MWF-RNO6 failed to induce an albuminuria phenotype either under control conditions or in response to a 50% nephron reduction after Nx in consomic SHR-6 MWF . 145 …”