Temporal characterization of the development of renal injury in FHH rats and FHH.1^BNcongenic strains

Abstract

The present study examined the effect of transfer of portions of chromosome 1 that includes (FHH.1(BN) AR(+) strain) or excludes (control FHH.1(BN) AR(-) strain) a 4.3-Mb region from the Brown Norway (BN) rat that restores the autoregulation (AR) of renal blood flow (RBF) on the development of hypertension and renal injury in congenic strains of Fawn Hooded Hypertensive (FHH) rats. FHH and control AR(-) rats exhibited poor autoregulation of RBF, and glomerular capillary pressure (Pgc) rose by 19 ± 2 mmHg in FHH rats when renal perfusion pressure (RPP) was increased from 100 to 150 mmHg. In contrast, RBF was well autoregulated in the AR(+) strain, and Pgc only increased by 3 ± 1 mmHg when RPP was increased over this range. Baseline mean arterial pressure (MAP) at 12 wk of age was similar in all strains and averaged 122 mmHg. MAP increased significantly in FHH rats and was significantly higher by 12 mmHg in 21-wk-old FHH rats than in the FHH.1(BN) congenic strains. Protein excretion rose from 5 ± 1 to 397 ± 29 mg/day in 6- vs. 21-wk-old FHH rats. In contrast, protein excretion only increased to 139 ± 21 mg/day in the control AR(-) strain, and it did not increase significantly in the AR(+) strain. Glomerular permeability to albumin was similar in all strains at 6 wk of age. It increased significantly in 9-wk-old FHH and control AR(-) rats, but not in the AR(+) strain. The levels of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-β2 protein were significantly higher in the renal cortex of 9-wk-old FHH rats compared with the levels seen in the AR(+) strain. These data indicate that transfer of a 4.3-Mb region of BN chromosome 1 into the FHH genetic background improves autoregulation of RBF, normalizes Pgc, and slows the progression of renal disease.

Mapping genetic determinants of kidney damage in rat models

“…Thus, in the congenic FHH.1 BN AR þ strain autoregulation of renal blood flow was normalized and a decrease in the progression of renal disease was observed (Table 2). 91,103 It was suggested that before hypertension occurred an impaired autoregulation in FHH may lead to early onset of renal disease such as glomerulosclerosis and renal interstitial fibrosis. 103 The genetic basis of albuminuria linked to the Rf-2 on RNO1 was elucidated by identifying Rab38 (RAB38, member RAS oncogene family) as a potential candidate gene within this locus.…”

“…91,103 It was suggested that before hypertension occurred an impaired autoregulation in FHH may lead to early onset of renal disease such as glomerulosclerosis and renal interstitial fibrosis. 103 The genetic basis of albuminuria linked to the Rf-2 on RNO1 was elucidated by identifying Rab38 (RAB38, member RAS oncogene family) as a potential candidate gene within this locus. 104 An Table 4.1 Distribution of QTL associated with renal (disease) phenotypes in the rat genome.…”

Genetic basis of the impaired renal myogenic response in FHH rats

“…1, restored autoregulation (48). The goal of the present study was to create additional double subcongenic strains to narrow the region of interest further so that positional candidate genes could be prioritized by sequencing and expression studies.…”

“…kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48). Genetic cosegregation studies identified five quantitative trait loci (QTLs) linked to the development of proteinuria in F2 crosses of FHH and AugustCopenhagen inbred (ACI) rats (4 -5, 36).…”

“…In contrast, autoregulation of RBF was not restored in a congenic strain in which only the 99.4-Mbp region of RNO1 containing the Rf-2 region was introgressed. Subsequently, we developed a subcongenic strain that narrowed the region of interest for autoregulation of RBF from 12.9 to a smaller 4.7-Mbp region of RNO1 (48). However, this region was still too large for positional cloning of the genes involved, and studies using this double congenic strain are open to the criticism that the restoration of the RBF autoregulation phenotype could be due to an interaction of genes in the two independent introgressed regions of BN RNO1.…”