Temporal characterization of the development of renal injury in FHH rats and FHH.1BN congenic strains.
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.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Jan Michael
JM
Williams
Marilyn
M
Burke
Jozef
J
Lazar
Howard J
HJ
Jacob
Richard J
RJ
Roman
D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D018014:Gene Transfer Techniques; D005919:Glomerular Filtration Rate / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006977:Hypertension, Renal / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics*; D007678:Kidney Glomerulus / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D011507:Proteinuria / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D012079:Renal Circulation / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000032:analysis
D053781:Transforming Growth Factor beta2; D020778:Matrix Metalloproteinase 2