Identification of a QTL on chromosome 1 for impaired autoregulation of RBF in fawn-hooded hypertensive rats

2006 ◽  
Vol 290 (5) ◽  
pp. F1213-F1221 ◽  
Author(s):  
Bernardo López ◽  
Robert P. Ryan ◽  
Carol Moreno ◽  
Albert Sarkis ◽  
Jozef Lazar ◽  
...  
Keyword(s):  
Genetic Background ◽  
Significant Quantitative Trait Locus ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Genetic Linkage Analysis ◽  
Hypertensive Rats ◽  
Congenic Strains ◽  
Protein Excretion ◽  
Trait Locus ◽  
Consomic Strain

The present study evaluated whether the impairment in autoregulation of renal blood flow (RBF) in the fawn-hooded Hypertensive (FHH) rat colocalizes with the Rf-1 region on chromosome 1 that has been previously linked to the development of proteinuria in this strain. Autoregulation of RBF was measured in FHH and a consomic strain (FHH.1BN) in which chromosome 1 from the Brown-Norway (BN) rat was introgressed into the FHH genetic background. The autoregulation indexes (AI) averaged 0.80 ± 0.08 in the FHH and 0.19 ± 0.05 in the FHH.1BN rats. We next performed a genetic linkage analysis for autoregulation of RBF in 85 F2 rats generated from a backcross of FHH.1BN consomic and FHH rats. The results revealed a significant quantitative trait locus (QTL) with a peak logarithm of the odds score of 6.3 near marker D1Rat376. To confirm the existence of this QTL, five overlapping congenic strains were created that spanned the region from markers D1Rat234 to D1Mit14. Transfer of a region of BN chromosome 1 from markers D1Mgh13 to D1Rat89 into the FHH genetic background improved autoregulation of RBF (AI = 0.23 ± 0.04) and reduced protein excretion. In contrast, RBF was poorly autoregulated and the rats were not protected from proteinuria in congenic strains in which other regions of chromosome 1 that exclude the D1Rat376 marker were transferred. These results indicate that there is a gene(s) that influences autoregulation of RBF and proteinuria between markers D1Mgh13 and D1Rat89 on chromosome 1 that lies within the confidence interval of the Rf-1 QTL previously linked to the development of proteinuria in FHH rats.

scholarly journals Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

2012 ◽  
Vol 302 (10) ◽  
pp. R1209-R1218 ◽  
Author(s):  
Jan M. Williams ◽  
Fan Fan ◽  
Sydney Murphy ◽  
Carlos Schreck ◽  
Jozef Lazar ◽  
...  
Keyword(s):  
Genetic Background ◽  
Chronic Administration ◽  
Brown Norway ◽  
Glomerular Injury ◽  
Chromosome 5 ◽  
Norway Rat ◽  
Protein Excretion ◽  
Elevated Expression ◽  
Brown Norway Rat ◽  
Consomic Strain

This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5BN (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 ± 1 to 183 ± 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 ± 5 mmHg in SS.5BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5BN rats compared with SS rats. Protein excretion rose to 354 ± 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 ± 13 mg/day in the SS.5BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5BN rats (43 ± 1 mmHg) and Dahl S (44 ± 2 mmHg) rats. However, Pgc increased to 59 ± 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5BN rats (43 ± 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg−1·day−1 iv) reversed the antihypertensive phenotype seen in the SS.5BN rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5BN consomic strain.

scholarly journals Temporal characterization of the development of renal injury in FHH rats and FHH.1BN congenic strains

2011 ◽  
Vol 300 (2) ◽  
pp. F330-F338 ◽  
Author(s):  
Jan Michael Williams ◽  
Marilyn Burke ◽  
Jozef Lazar ◽  
Howard J. Jacob ◽  
Richard J. Roman
Keyword(s):  
Renal Injury ◽  
Transforming Growth Factor ◽  
Renal Perfusion ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Glomerular Permeability ◽  
Congenic Strains ◽  
Protein Excretion ◽  
And Control ◽  
Progression Of Renal Disease

The present study examined the effect of transfer of portions of chromosome 1 that includes (FHH.1BN AR+ strain) or excludes (control FHH.1BN 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.1BN 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.

scholarly journals Genetic basis of the impaired renal myogenic response in FHH rats

2013 ◽  
Vol 304 (5) ◽  
pp. F565-F577 ◽  
Author(s):  
Marilyn Burke ◽  
Malikarjuna Pabbidi ◽  
Fan Fan ◽  
Ying Ge ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Renal Vasculature ◽  
Congenic Strains ◽  
Channel Current ◽  
Protein Excretion ◽  
Afferent Arterioles ◽  
Renal Vascular

This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K+ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K+ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K+ current, and slows the progression of proteinuria and renal injury.

Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains

2007 ◽  
Vol 31 (3) ◽  
pp. 458-462 ◽  
Author(s):  
Thomas N. Ferraro ◽  
George G. Smith ◽  
Candice L. Schwebel ◽  
Falk W. Lohoff ◽  
Patrick Furlong ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Genetic Background ◽  
Seizure Threshold ◽  
Maximal Electroshock ◽  
Seizure Susceptibility ◽  
Chromosome 5 ◽  
Congenic Strains ◽  
Combining Data ◽  
Trait Locus

Multiple quantitative trait locus (QTL) mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice have detected a significant effect originating from midchromosome 5. To confirm the presence and refine the position of the chromosome 5 QTL for maximal electroshock seizure threshold (MEST), reciprocal congenic strains between B6 and D2 mice were created by a DNA marker-assisted backcross breeding strategy and studied with respect to changes in MEST. A genomic interval delimited by marker D5Mit75 (proximal to the acromere) and D5Mit403 (distal to the acromere) was introgressed for 10 generations. A set of chromosome 5 congenic strains produced by an independent laboratory was also studied. Comparison of MEST between congenic and control (parental genetic background) mice indicates that genes influencing this trait were captured in all strains. Thus, mice from strains having D2 alleles from chromosome 5 on a B6 genetic background exhibit significantly lower MEST compared with control littermates, whereas congenic mice harboring B6 chromosome 5 alleles on a D2 genetic background exhibit significantly higher MEST compared with control littermates. Combining data from all congenic strains, we conclude that the gene(s) underlying the chromosome 5 QTL for MEST resides in the interval between D5Mit108 (26 cM) and D5Mit278 (61 cM). Generation of interval-specific congenic strains from the primary congenic strains described here may be used to achieve high-resolution mapping of the chromosome 5 gene(s) that contributes to the large difference in seizure susceptibility between B6 and D2 mice.

Nephron deficit is not required for progressive proteinuria development in the Munich Wistar Frömter rat

2008 ◽  
Vol 35 (1) ◽  
pp. 30-35 ◽  
Author(s):  
Angela Schulz ◽  
Jonna Hänsch ◽  
Kristina Kuhn ◽  
Maria Schlesener ◽  
Peter Kossmehl ◽  
...  
Keyword(s):  
Mild Hypertension ◽  
Genetic Model ◽  
Fold Increase ◽  
Chromosome 8 ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Trait Locus ◽  
Consomic Strain ◽  
Nephron Deficit

The Munich Wistar Frömter (MWF) rat represents a genetic model with an inherited nephron deficit and exhibits mild hypertension and progressive albuminuria, which is more pronounced in males than females. Previously, we demonstrated in a consomic strain that replacement of a quantitative trait locus on chromosome 6 normalized the nephron deficit and suppressed albuminuria development, suggesting a link between the two findings. Here we tested the role of a second major locus linked to albuminuria in MWF on chromosome 8 and generated the consomic strain MWF-8SHR by transfer of chromosome 8 from spontaneously hypertensive rats (SHR) into MWF. The early onset of albuminuria at 8 wk of age in MWF (>50-fold increase compared with SHR) was significantly suppressed in consomic animals, and the development of marked proteinuria at 32 wk significantly diminished. Total nephron number in consomic rats (23,771 ± 1,352) and MWF (27,028 ± 1,322) were similar and significantly lower (−36%) compared with SHR (36,979 ± 1,352, P < 0.0001). The development of mild albuminuria in female MWF was also significantly diminished in MWF-8SHR. Thus, the development of overt and mild albuminuria in male and female MWF rats is not a mandatory consequence of the inherited nephron deficit. The locus on chromosome 8 appears of interest, because its exchange between MWF and SHR protects against the development of albuminuria in MWF-8SHR animals despite their inherited nephron deficit and higher systolic blood pressure.

Substitution of chromosome 1 ameliorates l-NAME hypertension and renal disease in the fawn-hooded hypertensive rat

2005 ◽  
Vol 288 (5) ◽  
pp. F1015-F1022 ◽  
Author(s):  
David L. Mattson ◽  
Mary Pat Kunert ◽  
Richard J. Roman ◽  
Howard J. Jacob ◽  
Allen W. Cowley
Keyword(s):  
Renal Disease ◽  
Genetic Background ◽  
Female Rats ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Male And Female ◽  
Arterial Blood ◽  
Male And Female Rats ◽  
Induced Hypertension ◽  
Excretion Rates

Linkage analysis studies previously identified genetic loci associated with proteinuria and hypertension on chromosome 1 of fawn-hooded hypertensive (FHH) rats. The present studies were performed on conscious male and female rats to evaluate the influence of transfer of chromosome 1 from the Brown Norway (BN) rat to the FHH genetic background (FHH-1BN). Rats were maintained for 2 wk on 8.0% NaCl chow with NG-nitro-l-arginine methyl ester (l-NAME) in the drinking water (12.5 mg/l) to induce hypertension and accelerate the onset of renal disease. Mean arterial blood pressure (MAP) was significantly higher in the male FHH (188 ± 3 mmHg, n = 13) compared with the BN (121 ± 3 mmHg, n = 8); MAP in the FHH-1BN was midway between the two parental strains (167 ± 5 mmHg, n = 9). Urinary protein and albumin excretion rates in the male FHH-1BN (Uprot = 189 ± 36 mg/day, Ualb = 69 ± 16 mg/day, n = 10) were also midway between levels observed in the FHH (Uprot = 485 ± 54 mg/day; Ualb = 206 ± 25 mg/day, n = 13) and the BN (Uprot = 32 ± 5 mg/day, Ualb = 5 ± 1 mg/day, n = 8). Creatinine clearance was elevated, and the degree of glomerular damage was significantly reduced in the FHH-1BN compared with the FHH. Qualitatively similar results were obtained from female FHH, FHH-1BN, and BN rats. The present results indicate that genes contributing to l-NAME-induced hypertension and renal disease are found on chromosome 1 of the FHH rat.

scholarly journals Reciprocal congenic lines for a major stroke QTL on rat chromosome 1

2006 ◽  
Vol 27 (2) ◽  
pp. 108-113 ◽  
Author(s):  
Speranza Rubattu ◽  
Norbert Hubner ◽  
Ursula Ganten ◽  
Anna Evangelista ◽  
Rosita Stanzione ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Chromosome 1 ◽  
Spontaneously Hypertensive ◽  
Congenic Lines ◽  
Protein Excretion ◽  
Low Potassium ◽  
Trait Locus ◽  
Rat Genome ◽  
Japanese Diet ◽  
Major Stroke

We previously identified a quantitative trait locus (QTL) for stroke proneness between the kallikrein ( Klk) and Mt1pa markers on rat chromosome 1. To gain functional insights, we constructed congenic strains by introgressing either the whole or selected chromosomal segments from the stroke-prone (SHRsp) onto the stroke-resistant (SHRsr) spontaneously hypertensive rat genome and vice versa. The phenotype was the latency to develop stroke under a Japanese high-salt, low-potassium diet for 3 mo [known as Japanese diet (JD)]. Blood pressure (BP) was measured by tail cuff throughout the experiment. Urinary protein excretion was monitored in all lines under JD. The SHRsp-derived lines carrying the SHRsr allele, and particularly the D1Rat134- Mt1pa chromosomal segment, had a significant delay of stroke occurrence and improved survival compared with SHRsp ( P < 0.001). On the other hand, a significant occurrence of stroke events (20%) was detected in the reciprocal lines by the end of the 3-mo treatment with JD ( P = 0.003). The stroke phenotype was also associated with increased proteinuria. Our results underscore the functional importance of the Chr 1 stroke QTL. Furthermore, they underscore the utility of stroke/congenic lines in dissecting the genetics of stroke.

scholarly journals Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains

1999 ◽  
Vol 1 (3) ◽  
pp. 119-125 ◽  
Author(s):  
YASSER SAAD ◽  
MICHAEL R. GARRETT ◽  
SOON JIN LEE ◽  
HOWARD DENE ◽  
JOHN P. RAPP
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Chromosome 1 ◽  
Congenic Strains ◽  
Salt Hypertension ◽  
Trait Locus

Saad, Yasser, Michael R. Garrett, Soon Jin Lee, Howard Dene, and John P. Rapp. Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains. Physiol. Genomics 1: 119–125, 1999.—We previously reported that markers on rat chromosome 1 are genetically linked to blood pressure in an F2 population derived from Dahl salt hypertension-sensitive (S) and Lewis (LEW) rats. Because there was evidence for more than one blood pressure quantitative trait locus (QTL) on chromosome 1, an initial congenic strain introgressing a large 118-centimorgan (cM) segment of LEW chromosome 1 into the S background had been constructed. This initial congenic strain had a reduced blood pressure compared with S rats, proving the existence of a blood pressure QTL, but not giving a good localization of the QTL. In the present work a series of five overlapping congenic substrains were produced from the original congenic strain in order to localize a blood pressure QTL to a 25-cM region near the center of chromosome 1. The congenic substrains also ruled out the Sa locus as a blood pressure QTL in the S vs. LEW comparison because the Sa locus was contained in a congenic substrain that did not alter blood pressure.

scholarly journals Identification of a region of rat chromosome 1 that impairs the myogenic response and autoregulation of cerebral blood flow in fawn-hooded hypertensive rats

2013 ◽  
Vol 304 (2) ◽  
pp. H311-H317 ◽  
Author(s):  
Mallikarjuna R. Pabbidi ◽  
Julio Juncos ◽  
Luis Juncos ◽  
Marija Renic ◽  
Hurtis J. Tullos ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Reactivity ◽  
Cerebral Arteries ◽  
Cerebral Injury ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Edema Formation ◽  
Congenic Strains

This study examined the effects of transfer of a 2.4-Mbp region of rat chromosome 1 (RNO1) from Brown Norway (BN) into fawn-hooded hypertensive (FHH) rats on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of middle cerebral arteries (MCAs). AR of CBF was poor in FHH and FHH.1BN AR− congenic strains that excluded the critical 2.4-Mbp region. In contrast, AR was restored in FHH.1BN AR+ congenic strains that included this region. The diameter of MCAs of FHH rats increased from 140 ± 14 to 157 ± 18 μm when transmural pressure was increased from 40 to 140 mmHg, but it decreased from 137 ± 5 to 94 ± 7 μm in FHH.1BN AR+ congenic strains. Transient occlusion of MCAs reduced CBF by 80% in all strains. However, the hyperemic response following ischemia was significantly greater in FHH and AR− rats than that seen in AR+ congenic strains (AR−, 173 ± 11% vs. AR+, 124 ± 5%). Infarct size and edema formation were also significantly greater in an AR− strain (38.6 ± 2.6 and 12.1 ± 2%) than in AR+ congenic strains (27.6 ± 1.8 and 6.5 ± 0.9%). These results indicate that there is a gene in the 2.4-Mbp region of RNO1 that alters the development of myogenic tone in cerebral arteries. Transfer of this region from BN to FHH rats restores AR of CBF and vascular reactivity and reduces cerebral injury after transient occlusion and reperfusion of the MCA.

scholarly journals Verification and dissection of one quantitative trait locus for grain size and weight on chromosome 1 in rice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi-chen Cheng ◽  
Guan Li ◽  
Man Yin ◽  
Tosin Victor Adegoke ◽  
Yi-feng Wang ◽  
...  
Keyword(s):  
Grain Size ◽  
Quantitative Trait ◽  
Genetic Background ◽  
Molecular Design ◽  
Chromosome 1 ◽  
Recurrent Parent ◽  
Isogenic Line ◽  
Growing Seasons ◽  
Ril Population ◽  
Trait Locus

AbstractGrain size and weight are the key traits determining rice quality and yield and are mainly controlled by quantitative trait loci (QTL). In this study, one minor QTL that was previously mapped in the marker interval of JD1009-JD1019 using the Huanghuazhan/Jizi1560 (HHZ/JZ1560) recombinant inbred line (RIL) population, qTGW1-2, was validated to regulate grain size and weight across four rice-growing seasons using twenty-one near isogenic line (NIL)-F2 populations. The twenty-one populations were in two types of genetic background that were derived from the same parents HHZ and JZ1560. Twelve F9, F10 or F11 NIL-F2 populations with the sequential residual heterozygous regions covering JD1009-RM6840 were developed from one residual heterozygote (RH) in the HHZ/JZ1560 RIL population, and the remaining nine BC3F3, BC3F4 or BC3F5 NIL-F2 populations with the sequential residual heterozygous regions covering JD1009-RM6840 were constructed through consecutive backcrosses to the recurrent parent HHZ followed with marker assistant selection in each generation. Based on the QTL analysis of these genetic populations, qTGW1-2 was successfully confirmed to control grain length, width and weight and further dissected into two QTLs, qTGW1-2a and qTGW1-2b, which were respectively narrowed down to the marker intervals of JD1139-JD1127 (~ 978.2-kb) and JD1121-JD1102 (~ 54.8-kb). Furthermore, the two types of NIL-F2 populations were proved to be able to decrease the genetic background noise and increase the detection power of minor QTL. These results provided an important basis for further map-based cloning and molecular design breeding with the two QTLs in rice.

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