Chromosome 1 blood pressure QTL region influences renal function curve and salt sensitivity in SHR
MING LO1,
KIAO LING LIU1,
JENNIFER-REBECCA CLEMITSON2,
JEAN SASSARD1 and
NILESH J. SAMANI2
1 Département de Physiologie et Pharmacologie Clinique, Centre National de la Recherche Scientifique UMR 5014, Faculté de Pharmacie, 69373 Lyon cedex 08, France;
2 Department of Cardiology, Glenfield General Hospital, University of Leicester, Leicester LE3 9QP, United Kingdom
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ABSTRACT
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One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in the vicinity of the Sa gene. The present work examined whether this QTL region: 1) alters pressure-natriuresis relationship and 2) affects the BP response to salt load. Male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and rats from an SHR congenic strain that contains a WKY chromosome 1 segment spanning the BP QTL region (SHR. WKY-Sa) were used. In an acute study in anesthetized animals, renal function was measured at several levels of renal perfusion pressure. In a chronic study, BP was measured in freely moving rats using telemetry during normal and high sodium intake (2% NaCl as drinking water for 2 wk). WKY rats showed a significantly higher glomerular filtration rate and increased pressure-natriuresis compared with SHR. SHR.WKY-Sa also demonstrated an increased glomerular filtration rate and enhanced pressure-natriuresis, associated with a lower tubular sodium reabsorption, compared with SHR. These modifications were accompanied by a lower basal BP in SHR.WKY-Sa compared with SHR and a markedly reduced BP response to salt load. These findings suggest that the BP QTL(s) present in this region of chromosome 1 influences BP and salt sensitivity, at least partly, by modulating pressure-natriuresis.
genetic hypertension; congenic strain; kidney
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INTRODUCTION
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STRONG EVIDENCE HAS BEEN GATHERED for the presence of one or more quantitative trait loci (QTLs) affecting blood pressure (BP) on rat chromosome 1 in the proximity of the Sa gene. Apart from linkage of chromosome 1 markers to BP phenotypes in several crosses of hypertensive and normotensive rats (9, 12, 13, 16, 27), more recent work has confirmed the existence of several BP QTLs on chromosome 1 by their capture in congenic strains (3, 10, 14, 25, 28). In the second filial (F2) generation of a cross of the spontaneously hypertensive rat (SHR) with the normotensive Wistar-Kyoto (WKY) rat, we mapped a BP QTL region on chromosome 1 with a peak "logarithm of the odds ratio" (LOD) score of 6.7 that accounted for a quarter of the genetic variance of BP in the cross (3, 27). By reciprocal transfer of the relevant region between SHR and WKY rats through more than 10 marker selected back-crosses, we have captured and confirmed the existence of the QTL in congenic strains (3). Since, genetically, a congenic strain only differs from the respective parental for the introgressed segment, it provides a powerful resource to investigate the functional and physiological disturbances associated with the QTLs effect on the primary phenotype, BP in this case.
Transplantation studies using kidneys from SHR and WKY rats have provided strong evidence that the genetic basis of hypertension in the SHR is at least partly mediated via the kidney. Thus bilaterally nephrectomized SHR x WKY F1 animals that receive a kidney from the SHR develop a BP that is significantly greater than that of animals that receive a kidney from the WKY rat, even when the SHR donor is young (prehypertensive) or has been pretreated since weaning with anti-hypertensive drugs to prevent secondary effects due to renal damage (21). In view of this, we hypothesized that the chromosome 1 BP QTL region may act via the kidney. If this is the case, then it would be anticipated to affect pressure-natriuresis, which is the major determinant of BP (6, 7), and to consequently modulate the BP response to an increased salt intake. In this study, we therefore sought to investigate the effect of the chromosome 1 BP QTL region on these parameters.
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METHODS
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Animals.
Three groups of male rats were studied. SHR and WKY progenitor strains and a SHR congenic strain (SHR. WKY-D1Wox33/D1Got194, hereafter called SHR.WKY-Sa) containing a WKY chromosome 1 region including the BP QTL (3). The introgressed region from the WKY is shown in Fig. 1. Homozygosity for SHR alleles over the rest of the genome was confirmed by testing over 80 randomly distributed markers polymorphic between SHR and WKY (3). Animals were housed in controlled conditions (temperature, 21 ± 1°C; humidity, 60 ± 10%; lighting, 820 h), fed a standard rat chow containing 0.25% sodium (Special Diet Services, Witham Essex, UK) and received tap water ad libitum. The studies were conducted in agreement with our institutional guidelines for animal care.

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Fig. 1. Shows the segment of chromosome 1 from the Wistar-Kyoto rat (WKY) introgressed into spontaneously hypertensive rat (SHR) in SHR.WKY-Sa. Selected markers polymorphic between SHR and WKY are shown on the left, and known genes located within the region are on the right. Marker and gene positions have been assimilated from several sources including Frantz et al. (2, 3), Watanabe et al. (30), Kaisaki et al. (15) and the web sites http://www.well.ox.ac.uk, http://ratmap.gen.gu.se, and http://rgd.mcw.edu. The black area is definitely congenic. The gray zones represent the regions of uncertainty. On the centromeric side this is small. On the telomeric side, the region is relatively long because of the unusual lack of polymorphism between SHR and WKY in over 50 markers located in this region (see Ref. 2). Gene abbreviations (in alphabetical order): Acadsb, acyl-coenzyme A dehydrogenase, short-branched chain; Adam12, disintegrin and metalloproteinase domain 12, meltrin alpha; Adm, adrenomedullin precursor; Aldoa, aldolase A, fructose-bisphosphate; Ampd3, adenosine monophosphate deaminase 3; Calca, calcitonin/calcitonin-related polypeptide, alpha; Ccnd1, cyclin D1; Cd151, CD151 antigen; Cox6a2, cytochrome c oxidase subunit VIa polypeptide 2; Ctsd, cathepsin D (lysosomal aspartyl protease); Drd4, dopamine receptor D4; Echs1, enoyl-CoA hydratase, short chain 1, mitochondrial; Fgfr2, fibroblast growth factor receptor 2; Fkh15, HNF3/forkhead homolog 5; Gal, galanin; Gstp1, glutathione-S-transferase, placental enzyme pi type; Hras, Harvey rat sarcoma viral (v-Ha-ras) oncogene homolog; Igf2, insulin-like growth factor II (somatomedin A); Il4r, interleukin 4 receptor; Ins2, insulin; Itgam, Integrin- M; Mgmt, O6-methylguanine-DNA methyltranferase; Mt1p1, metallothionein; Myl2, myosin, light polypeptide 2, alkali, ventricular, skeletal, slow; Muc5ac, mucin 5, subtypes A and C, tracheobronchial/gastric; Oat, ornithine aminotransferase; Pde3b, adipocyte hormone-sensitive, cGMP phosphodiesterase B; Plcb3, phospholipase C, ß3; Prkcb1, protein kinase C-ß; Prkm3, protein kinase, mitogen-activated 3 (extracellular-signal-regulated kinase 1, ERK1); Pth, parathyroid hormone; Ptpre, protein tyrosine phosphatase, receptor type, epsilon polypeptide; Pygm, phosphorylase, glycogen muscle; Rnh, ribonuclease inhibitor; Scnn1b, sodium channel, non-voltage-gated 1, beta (epithelial); Sct, secretin; Spn, sialophorin (gpL115) leukosianin, CD43; Stm, sulftransferase, monoamine preferring; Th, tyrosine hydroxylase; Tnnt3, troponin T, fast skeletal; Tub, tubby (mouse homolog).
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Renal function curve.
Pressure-natriuresis was acutely studied in adult rats (26 ± 1 wk) using the widely used method of Roman and Cowley (23). Briefly, the right kidney and adrenal gland were removed, and the rats were allowed 710 days to recover. On the day of experiment, the rats were anesthetized with Inactin (70 mg/kg ip; Research Biochemicals International, Natick, ME) and ketamine (30 mg/kg ip; Sigma Chemical, St. Louis, MO) and placed on a heating blanket (model 50-6980; Harvard Apparatus, Edenbridge, KY) to maintain the rectal temperature at 37 ± 0.5°C. The left jugular vein was cannulated for infusions. Catheters placed into the left carotid and femoral arteries were used to sample blood and record the BP through a pressure transducer (model P23ID; Statham Instrument Division, Gould, Cleveland, OH). The left kidney was denervated, the remaining adrenal gland was removed, and the left ureter was cannulated for urine collection. Two adjustable Silastic balloon cuffs were placed around the aorta, one above and the other below the left renal artery, so that the renal perfusion pressure could be fixed at different levels. Silk ligatures were placed loosely around the superior mesenteric and celiac arteries and tightened to further elevate the renal perfusion pressure. An ultrasonic flow probe was placed around the left renal artery to continuously record the total renal blood flow using a transit-time flowmeter (model T106; Transonic Systems, Ithaca, NY). After a priming dose (250 mg/kg iv) of polyfructosan (Inutest; Laevosan, Linz, Austria), a hormone cocktail designed to stabilize the circulating levels of the most important sodium- and water-retaining hormones was infused at a rate of 330 µl·kg-1·min-1. It contained D-aldosterone (66 ng·kg-1·min-1), hydrocortisone (33 ng· kg-1·min-1), norepinephrine (333 ng·kg-1·min-1), and [Arg8]vasopressin acetate (0.17 ng·kg-1·min-1). Drugs were obtained from Sigma Chemical and dissolved in 0.9% sodium chloride containing 1% bovine serum albumin (fraction V) and 1.25% polyfructosan. Ninety minutes after the start of the hormone cocktail infusion, renal perfusion pressure was set to 110 mmHg for WKY and to 140 mmHg for SHR and SHR.WKY-Sa. After a 10-min equilibration period, urine was collected for 20 min, and arterial blood was sampled at the end of the period. Then renal perfusion pressure was increased to 140 and 170 mmHg in WKY and to 170 and 200 mmHg in SHR and SHR.WKY-Sa by ligating the superior mesenteric and celiac arteries and by inflating the infrarenal aortic cuff respectively. At each renal perfusion pressure level, urine was collected for 10 min, and arterial blood was sampled at the end of period. Each volume of blood drawn (200 µl) was compensated by an equivalent volume of 0.9% sodium chloride. At the end of the experiment, the left kidney was decapsulated, removed, cut in half, blotted dry, and weighed. Renal parameters were corrected for the weight of the left kidney. Renal perfusion pressure was estimated as the mean femoral artery pressure when the suprarenal aortic cuff was inflated and as the mean carotid artery pressure when the infrarenal aortic cuff was inflated. Renal vascular resistance was calculated as the ratio of renal perfusion pressure to renal blood flow. Glomerular filtration rate was measured by polyfructosan clearance. Urine flow was determined by weighing, and sodium concentration was measured by flame photometry (IL meter, model 243; Instrumentation Laboratory, Lexington, ME).
Blood pressure and its responses to salt load.
At 17 wk of age, animals were instrumented for telemetric BP recording. The telemetric radio transmitter (model TA11PA-C40; Data Sciences International, St. Paul, MN) was implanted as previously described (1). Briefly, rats were anesthetized with halothane (2% in oxygen). Through a midline abdominal incision, a fluid-filled sensor catheter was inserted in the aorta just above the iliac bifurcation. Rats received, during the three following days, a subcutaneous injection of penicillin G (50,000 U), then placed into individual cages for 2 wk of recovery. Experiments started in 19-wk-old animals. They lasted 8 wk, consisting of three successive periods: 4 wk of normal salt intake (diet containing 0.25% sodium + tap water); 2 wk of high salt intake (diet containing 0.25% sodium + 2% NaCl as drinking water), and finally 2 wk of normal salt intake. During the whole study, BP was recorded once a week for 22 consecutive hours (from 9 h to 7 h of the next morning). BP was monitored using a computerized system (LabView Software; National Instruments, Austin, TX). BP curve was sampled every 2 ms during 22 h and stored on CD-ROM. Offline data processing was performed with a workstation (Sun Microsystems, Mountain View, CA) so as to obtain beat-to-beat values of systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) and to perform statistical analyses (5).
Statistical analysis.
Values are means ± SE. In the acute renal function curve study, one-way ANOVA for repeated measures was used to evaluate the effects of renal perfusion pressure within groups. The differences between groups at a given level of renal perfusion pressure (140 and 170 mmHg) were assessed using Students t-test for unpaired data. In the chronic study, the differences in BP between groups were analyzed by Mann and Whitney test.
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RESULTS
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Renal function curve.
The effects of increasing renal perfusion pressure on renal function are illustrated in Fig. 2. Table 1 shows the comparisons among three strains at two common levels of renal perfusion pressure (140 and 170 mmHg) studied in each of the three strains.

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Fig. 2. Effects of renal perfusion pressure (RPP) on renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), urinary volume (UV), urinary sodium excretion (UNaV), and fractional sodium reabsorption (RNa) in anesthetized SHR rats, WKY rats, and congenic SHR rats containing a WKY chromosome 1 region including the blood pressure (BP) quantitative trait locus (QTL) (SHR.WKY-Sa). *P < 0.05, **P < 0.01, and ***P < 0.001 SHR vs. WKY rats. P < 0.05 SHR.WKY-Sa vs. SHR.
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In WKY rats, a stepwise elevation in renal perfusion pressure from 110 to 170 mmHg (Fig. 2) did not modify renal blood flow and glomerular filtration rate, but increased renal vascular resistance (ANOVA, P < 0.05). In SHR, an elevation of renal perfusion pressure from 140 to 200 mmHg did not significantly alter renal blood flow, but significantly increased glomerular filtration rate (ANOVA, P < 0.05), especially at 200 mmHg of renal perfusion pressure related to a lack of autoregulation. In both WKY and SHR, an elevation in renal perfusion pressure increased diuresis and natriuresis and decreased sodium reabsorption. The pressure-diuresis and natriuresis curves were shifted to higher renal perfusion pressures in SHR. When the renal perfusion pressure was at 140 and 170 mmHg (Table 1), SHR differed from WKY rats by a significant decrease in renal blood flow (only at 170 mmHg) and glomerular filtration rate and an increase in renal vascular resistance. In SHR, the pressure-induced diuresis and natriuresis were significantly lower than in WKY rats.
In congenic rats, the introduction of a WKY chromosome 1 region including the BP QTL into SHR generally improved the renal function (Fig. 2). Interestingly, the autoregulation of glomerular filtration rate in SHR.WKY-Sa was ameliorated compared with SHR. When the renal perfusion pressure was at 140 and 170 mmHg (Table 1), SHR.WKY-Sa differed from SHR by a significantly higher glomerular filtration rate, an increased pressure-diuresis, and a more marked pressure-natriuresis. At the highest renal perfusion pressure (200 mmHg), a significantly decreased sodium reabsorption (P < 0.05) was observed in SHR.WKY-Sa.
Blood pressure and its responses to salt load.
Figure 3 shows the SBP, DBP, and HR evolutions during the day (from 9 h to 20 h) and night (from 20 h to 7 h of the next morning). During normal sodium intake, SHR exhibited a severe hypertension compared with WKY rats. SHR.WKY-Sa differed from SHR by a significantly lower SBP during both day and night, whereas their DBP were significantly decreased during the night only. HR did not differ among the three strains. When given 2% NaCl to drink, SBP and DBP progressively increased in SHR during day and night. This BP response to oral salt load was associated with an increase in HR. In WKY rats, daytime BP remained stable, whereas it increased modestly during nighttime, i.e., when the rats are active. HR was unchanged in WKY rats by salt load. In SHR.WKY-Sa, the BP changes induced by 2% NaCl were significantly blunted compared with SHR, and, as seen in WKY rats, salt load was not associated with an increase in HR. After cessation of salt load, BP and HR returned to preload values within 1 wk in the three strains.

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Fig. 3. Average values of systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) during normal and high salt intake (2% NaCl as drinking water) in freely moving SHR rats, WKY rats, and congenic SHR rats containing a WKY chromosome 1 region including the BP QTL (SHR.WKY-Sa). *P = 0.04 and **P = 0.02 SHR.WKY-Sa vs. SHR.
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DISCUSSION
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Mapping studies have identified many QTLs affecting BP in genetically hypertensive rats, and their isolation in congenic strains has been the main approach used for their further characterization (20). Apart from genetic analysis, congenic strains provide a powerful tool for identifying relevant intermediary phenotypes, since they only differ from control (parental) strains for a small fraction of the genome. Thus any differences seen are more likely to be involved in the physiological pathway(s) that regulates the trait of interest. In this study, we demonstrate for the first time that the rat chromosome 1 BP QTL region also influences pressure-natriuresis relationship, salt sensitivity, and most probably sympathetic activation following salt loading. These findings may be related and pertinent to the effect on BP.
Pressure-natriuresis was studied using the classic method designed by Roman and Cowley (23), which one allows to maintain, at a fixed level, most of the extrarenal factors that control renal sodium excretion, thus permitting an analysis of the intrinsic ability of the kidneys to excrete sodium. As previously reported (8, 22), the results showed that compared with WKY rats, SHR exhibit a reduced renal blood flow and glomerular filtration rate associated with an increased renal vascular resistance and a blunted pressure-diuresis and -natriuresis due to an increased tubular sodium reabsorption. Interestingly, SHR.WKY-Sa differed from SHR progenitors by an increased and better regulated glomerular filtration rate and a improved pressure-induced diuresis and natriuresis together with a lower tubular sodium reabsorption. Therefore, these renal changes obtained in acute and strictly controlled conditions demonstrate that introgression of the BP QTL region of WKY chromosome 1 enhances the ability of the SHR kidneys to excrete sodium.
We explored the possible physiological correlates of this, by studying the effect of changes in dietary salt intake on longitudinal BP in freely moving unrestricted animals using telemetry. The BP under basal conditions confirmed our previous observation (3) of a lower BP in SHR.WKY-Sa compared with SHR. Interestingly, differences were more marked at night than during the daytime, possibly reflecting the increased activity of the animals. Salt loading induced a progressive and marked increase in BP associated with a tachycardia in SHR. In WKY rats, the effect on BP was much more modest and only noticeable at night. Furthermore, it was not associated with any increase in HR. SHR.WKY-Sa also showed a much blunted BP response compared with SHR and again without any accompanying tachycardia. Also, by the second week of the high-salt diet, the BP response in the SHR.WKY-Sa had plateaued, indicating adaptation had occurred, whereas that in the SHR was still showing a progressive increase (Fig. 3). These findings demonstrate that the QTL region of rat chromosome 1 which affects BP also has a significant effect on salt sensitivity. Although we cannot fully exclude that different strains have variable appetite for salt, it is likely that the two effects are related and secondary to an alteration in the renal handling of sodium.
An interesting and somewhat unexpected finding was the blunting of the salt-induced tachycardia in the congenic strain. The differences cannot be attributed to any methodological problems as all animals were studied at the same time by telemetry and without any restraint or stress. Previous studies have shown that salt loading augments sympathetic activity in the SHR and that this is, at least in part, mediated by central impairment of the baroreceptor reflex (17, 18). Our present observation suggests that either the QTL itself or an adjacent locus also interferes with sodium-induced sympathetic activation.
An acknowledged limitation of pressure-natriuresis studies is that one cannot determine whether the renal function changes are primary or secondary to BP. However, interestingly, in the chronic part of our study, the BP response to salt load was not related to the baseline BP, e.g., the SHR.WKY-Sa strain had a 22-h SBP response (+16 mmHg) to salt load similar to that of WKY rats (+11 mmHg) while the difference in their baseline SBP exceeded 35 mmHg. Similarly, although the difference in baseline SBP between SHR and SHR. WKY-Sa rats was
15 mmHg, the 22-h SBP response to salt load in SHR (+49 mmHg) was markedly higher than in congenic SHR (+16 mmHg). These results strongly suggest that the renal defects are unlikely be entirely a consequence of hypertension and indeed may mediate the degree of salt sensitivity observed.
The findings of our study provide a strong impetus for looking at renally expressed genes to explain the BP effect and the effects on the associated phenotypes. In this context, it is important to appreciate that the effects observed may be the composite of multiple QTLs. Recent studies by Saad et al. (26) in congenic strains derived from the Dahl hypertensive rat and our own genetic dissection of the region around the Sa gene in SHR/WKY rats (2) has shown that there are multiple QTLs affecting BP in this region of chromosome 1. Whether the renal phenotypes reported here relate to one or several of these QTLs remains to be elucidated, and the availability of subcongenic strains (2) will facilitate this investigation. Several renally expressed genes or genes with renal effects are present within the congenic interval in SHR.WKY-Sa (Fig. 1). These include Sa, a gene of yet unknown function, which is highly expressed in the SHR kidney (11), especially in the proximal tubules (19, 31). Although recent studies in several congenic strains have shown that at least a part of BP effect of this chromosomal region maps away from the Sa gene (2, 10, 25, 26, 29), given its site of expression, it could nonetheless impact on the renal function curves studied here. Comparison of congenic substrains derived from SHR.WKY-Sa that include/exclude an introgressed Sa gene (2) should help to clarify any role. Another potential gene is the epithelial sodium channel, although preliminary studies have not demonstrated any structural alteration in this gene in different hypertensive models (4). Adrenomedullin, the natriuretic, diuretic, and vasoactive peptide, also maps to this QTL region (24). Further studies using microarray-based expression profiling techniques to compare gene expression in the SHR and SHR.WKY-Sa kidneys will likely identify further candidates.
In summary, for the first time we have demonstrated relevant intermediary phenotypes linked to the BP QTLs on rat chromosome 1. Our findings provide support on physiological evidence for investigating the kidney as the primary organ mediating the hemodynamic effect of these QTLs.
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ACKNOWLEDGMENTS
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This work has been supported by the British Heart Foundation, the EURHYPGEN II Concerted Action of the European Community, and the French Centre National de la Recherche Scientifique.
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FOOTNOTES
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Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: M. Lo, Département de Physiologie et Pharmacologie Clinique, Faculté de Pharmacie, 8 Ave. Rockefeller, 69373 Lyon Cedex 08, France (E-mail: mlo{at}rockefeller.univ-lyon1.fr).
10.1152/physiolgenomics.00057.2001.
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