Transfer of theRf-1region from FHH onto the ACI background increases susceptibility to renal impairment

Abstract

The genetically hypertensive fawn-hooded (FHH/Eur) rat is characterized by the early presence of systolic and glomerular hypertension, progressive proteinuria (UPV), and albuminuria (UAV), and focal glomerulosclerosis, resulting in premature death from renal failure. Previous studies showed that at least five genetic loci (Rf-1 to Rf-5) were linked to the development of renal impairment. Of these five, Rf-1 appears to play a major role. To study the impact of Rf-1 in the absence of the other loci, we transferred the Rf-1 region of chromosome 1, between the markers D1Mit34 and D1Rat156, Rf-1B for short, onto the genomic background of the normotensive August x Copenhagen Irish (ACI) rat. In this congenic strain, named ACI.FHH-D1Mit34/Rat156 or ACI.FHH-Rf1B, we challenged the renal hemodynamic function of these animals by studying the effects of unilateral nephrectomy (UNX) alone, or combined with N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Following UNX, the congenic strain developed significantly more UPV and UAV than the ACI progenitor. The differences were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mmHg, i.e., the level of hypertension present in the parental FHH strain. These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure.

Mapping genetic determinants of kidney damage in rat models

“…To enhance renal damage susceptibility, that is, albuminuria/proteinuria and focal glomerulosclerosis, in the resistant ACI background, however, animals were subjected to either unilateral nephrectomy (Nx) or NO inhibition by treatment with L-NAME or a combination of both procedures. [92][93][94][95][96] By using this protocol, different segments of the FHH-Rf-1 region in five subcongenic ACI strains directly aggravated indeed the susceptibility of kidney damage and the autoregulation in congenic rats (Table 2). [92][93][94][95][96] Thus, the Rf-1 locus contains at least one gene that might influence the susceptibility to progressive renal failure in the presence of higher BP values due to NO inhibition or Nx.…”

“…[92][93][94][95][96] By using this protocol, different segments of the FHH-Rf-1 region in five subcongenic ACI strains directly aggravated indeed the susceptibility of kidney damage and the autoregulation in congenic rats (Table 2). [92][93][94][95][96] Thus, the Rf-1 locus contains at least one gene that might influence the susceptibility to progressive renal failure in the presence of higher BP values due to NO inhibition or Nx. 92 Van Dijk et al 93,95,96 demonstrated in a congenic Rf-3 strain a slightly increased susceptibility to renal damage (Table 2), while single Rf-4 and Rf-5 congenics appeared normal in comparison with ACI, respectively.…”

“…[92][93][94][95][96] Thus, the Rf-1 locus contains at least one gene that might influence the susceptibility to progressive renal failure in the presence of higher BP values due to NO inhibition or Nx. 92 Van Dijk et al 93,95,96 demonstrated in a congenic Rf-3 strain a slightly increased susceptibility to renal damage (Table 2), while single Rf-4 and Rf-5 congenics appeared normal in comparison with ACI, respectively.…”

Rf-2 Gene Modulates Proteinuria and Albuminuria Independently of Changes in Glomerular Permeability in the Fawn-Hooded Hypertensive Rat

“…Congenic animals were developed by marker-assisted selective breeding of FHH and BN rats as reported previously (25). Sequencing of positional candidate genes was performed using genomic DNA and cDNA on an ABI3730 capillary sequencer according to the manufacturer's suggested protocol.…”

Enhanced expression of EGF receptor in a model of salt-sensitive hypertension

“…For example, the risk of development of end-stage renal disease is greater in black, compared with non-black, hypertensive patients (23, 25). Recent evidence from animal models of hypertension supports a genetic basis for susceptibility to end-organ kidney damage (2,9,10,12,24). While the genes responsible for development of hypertensive renal disease have not been elucidated, the pathological changes that typically occur represent an arteriolopathic process, and it is logical to hypothesize that the responsible genetic alterations affect the renal vascular response to hypertension.…”