Hypertension Research

Review

Remission and Regression of Diabetic Nephropathy

Hirofumi MAKINO, Yoshio NAKAMURA, Jun WADA

Article type: Review
2003 Volume 26 Issue 7 Pages 515-519
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.515

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Diabetic nephropathy has become the single largest cause of end-stage renal disease (ESRD) worldwide. Until recently, it was thought that once a patient developed overt proteinuria, diabetic nephropathy was irreversible and inevitably progressed to ESRD. However, the reversal of lesions caused by diabetic nephropathy (e.g., glomerular basement membrane thickening and mesangial matrix increase) has been demonstrated in a series of patients who underwent a pancreas transplantation 10 years prior to the reversal. Remission of nephrotic range proteinuria has also been reported in some patients with type 1 diabetes from the Collaborative Study Group during a median follow-up of 3 years of angiotensin-converting enzyme (ACE) inhibitor administration; no deterioration of renal function was observed in these patients. Remission and regression in nephropathy of type 1 diabetes patients have also been reported when blood pressure was controlled aggressively. Recent clinical trials have demonstrated that angiotensin II receptor blocker (ARB) preserved renal function and slowed the progression of nephropathy to ESRD in patients with type 2 diabetes. Since many patients with type 2 diabetes manifest with a metabolic syndrome, multifactorial intensive treatment is necessary; such treatment includes behavior modifications, dietary intervention, exercise, and smoking cessation. In this population, pharmacological therapy targeting hyperglycemia, hypertension (including ARB/ACE inhibitor), and hyperlipidemia in cases of type 2 diabetes is also necessary. (Hypertens Res 2003; 26: 515-519)

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Salt Sensitivity of Japanese from the Viewpoint of Gene Polymorphism

Tomohiro KATSUYA, Kazuhiko ISHIKAWA, Ken SUGIMOTO, Hiromi RAKUGI, Tosh ...

Article type: Review
2003 Volume 26 Issue 7 Pages 521-525
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.521

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Excess salt intake is an important environmental risk for the predisposition to essential hypertension. Previous physiological studies have shown that salt sensitivity is associated with insulin resistance, enhancement of sympathetic nerve activity and decrease of blood pressure decline at night. We have been examining the genetic importance of candidate gene polymorphisms of salt-sensitive hypertension using several populations. The angiotensinogen gene (AGT) is a thrifty gene which increases the risk for common disease with growth of civilization via sodium and body fluid retention. The CC genotype of the AGT/T+31C polymorphism, which is in complete linkage disequilibrium with the TT genotype of the M235T polymorphism, was associated with a decrease of blood pressure decline at night in the Ohasama Study. On the other hand, the Gly460Trp genotype of the α-adducin gene (ADD1) is associated with erythrocyte sodium transport and increases tubular sodium reabsorption and risk for hypertension. We also revealed in the Ohasama Study that the Trp460 allele of ADD1 is associated with hypertension in young subjects with low renin activity. In addition to these polymorphisms, the T(-344)C polymorphism in the promoter of the aldosterone synthase gene (CYP11B2) and the C825T polymorphism of the G-protein β3 subunit gene (GNB3) are considered candidates for the genetic risk of salt-sensitive hypertension. We compared the allele frequency of five candidate genes between Japanese and Caucasians; the results showed that the frequencies of all alleles were significantly higher in Japanese than in Caucasians. This interesting finding might suggest a feasible explanation for the huge interracial differences in the frequency of salt-sensitive hypertension. (Hypertens Res 2003; 26: 521-525)

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Chinese Medicine, Jiang-Tang-Ke-Li, Improves Insulin Resistance by Modulating Muscle Fiber Composition and Muscle Tumor Necrosis Factor-α in Fructose-Fed Rats

Ling WANG, Katsuhiro HIGASHIURA, Nobuyuki URA, Tetsuji MIURA, Kazuaki ...

Article type: Review
2003 Volume 26 Issue 7 Pages 527-532
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.527

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Insulin resistance and hyperinsulinemia are common findings in patients with essential hypertension. These impairments in glucose metabolism are commonly associated with diabetes mellitus, hypertension, and dyslipidemia, which are high risk factors of cardiovascular diseases, and recent evidence indicates that they may play a role in the development of coronary artery disease. The aim of this study was to determine the effect of Jiang-Tang-Ke-Li (JTKL), a traditional Chinese medicine used to treat diabetes mellitus in China, on insulin resistance and hypertension in fructose-fed rats (FFR). Systolic blood pressures in the FFR groups were significantly higher than that in the control group, although JTKL had no effect on systolic blood pressure for the last 2 weeks of treatment with the medicine. The average rate of glucose infusion during a glucose clamp, as an index of insulin sensitivity (M value), was significantly lower in the FFR than in the control rats, and treatment with JTKL for 2 weeks significantly increased the M value to that of the control. Treatment with Panax ginseng (PG), a component of JTKL, for 2 weeks also significantly increased the M value of FFR to the control level. The composite ratio of type I fibers in soleus muscle decreased significantly in the FFR compared to that in the control, and treatment with JTKL led to recovery of the composite ratio of type I fibers to the same level as that of the control group. The M value showed a significant positive correlation with the composite ratio of type I fibers and a significant negative correlation with the composite ratio of type II fibers. Tumor necrosis factor (TNF)-α levels were significantly higher in the soleus and extensor digitorum longus (EDL) muscles of the FFR than in those of the control rats. Treatment with JTKL for 2 weeks significantly lowered TNF-α levels to the control levels. M values showed a significant negative correlation with TNF-α in both the soleus and EDL muscles. The results suggest that the Chinese medicine JTKL, which contains PG as one of its valid components, improves insulin resistance by modulating muscle fiber composition and TNF-α in skeletal muscles in hypertensive and insulin-resistant FFR. (Hypertens Res 2003; 26: 527-532)

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Original Articles

Clinical studies

Genome-Wide Linkage Disequilibrium Mapping of Hypertension in Japan

Zhihong WU, Jun NAKURA, Michiko ABE, Jing-Ji JIN, Miyuki YAMAMOTO, Yus ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 7 Pages 533-540
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.533

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Hypertension is a common, complex phenotype resulting from the interaction between genetic and environmental factors. To select candidate regions potentially responsible for hypertension, we are conducting a genome-wide linkage disequilibrium (LD) mapping of hypertension using dinucleotide repeat markers in 146 hypertensive and 136 normotensive subjects. Although the LD mapping is still underway, 19 alleles of 15 markers have already shown a nominally significant association (p <0.05), with odds ratios ranging from 0.08 to 5.12, suggesting the presence of many hypertension-related loci with weak effects in the human genome. These markers should be further assessed, adjusting for confounding factors and considering gene-gene and gene-environmental interactions in additional samples. In this report, we discuss our ongoing LD mapping project and describe the 15 markers thus far discovered. Among the 15 markers, D10S537 had a highly significant association with hypertension (p =5.3×10^-5; OR=3.80; 95% CI=1.98-7.27; where OR indicates the odds ratio and 95% CI indicates the 95% confidence interval). Further analysis in a large Japanese population showed that D10S537 was significantly associated with hypertension (p =0.044; OR=1.27; 95% CI=1.01-1.59). D10S537 was more significantly associated with hypertension in subjects with normotriglyceridemia in our population (p =0.007; OR=1.47; 95% CI=1.11-1.95). (Hypertens Res 2003; 26: 533-540)

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Elevation of Serum C-Reactive Protein Levels Is Associated with Obesity in Boys

Makoto HIURA, Toru KIKUCHI, Keisuke NAGASAKI, Makoto UCHIYAMA

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 7 Pages 541-546
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.541

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This study aimed to reveal the relationships among C-reactive protein (CRP), obesity, blood pressure (BP), and serum lipids in children. Eighty-six obese and 58 non-obese boys aged an average of 11.2 years were examined. Serum CRP levels were measured by high sensitivity latex turbidimetric immunoassay and subjects with CRP levels below 0.3 mg/dl were adopted. Comparisons of serum CRP levels, BP, and serum lipids levels between age-matched obese and non-obese groups were performed. A comparison of serum CRP levels among the percentage of relative weight quartiles and the relationships among percentage of relative weight, BP, and serum lipids in CRP quartiles were analyzed. The relationships between CRP and other parameters were analyzed by simple and stepwise multiple regressions. Obese children had significantly higher high-sensitivity CRP (hs-CRP) levels than their non-obese counterparts. The mean hs-CRP level was 5.5-fold higher in the top quartile of the percentage of relative weight than in the bottom quartile. In the top quartile of CRP, the percentage of relative weight, systolic BP, diastolic BP, pulse pressure, and low density/high density lipoprotein-cholesterol (LDL-C/HDL-C) were significantly higher than in the bottom quartile. The percentage of relative weight, BP, LDL-C, and apolipoprotein B (ApoB) showed positive correlations and HDL-C showed a negative correlation with log CRP by simple regression. Stepwise multiple regression analysis indicated that only the percentage of relative weight was strongly related to CRP. In conclusion, this study revealed a significant relationship between CRP and obesity in children. Obese children tended to have high CRP levels, BP elevation, and slight dyslipidemia. These results support the findings that CRP is one of the useful indices of childhood obesity that would affect the progression to future atherosclerotic disease. We consider that a strategy of preventing obesity from childhood would contribute to a drop in the future incidence of metabolic syndromes. (Hypertens Res 2003; 26: 541-546)

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Association of Angiotensin II Type 2 Receptor Gene Variant with Hypertension

Jing-Ji JIN, Jun NAKURA, Zhihong WU, Miyuki YAMAMOTO, Michiko ABE, Yus ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 7 Pages 547-552
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.547

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The renin-angiotensin system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. Angiotensin II, the major biologically active component of this system, exerts its effect via two pharmacologically distinct subtypes of angiotensin II receptors, the angiotensin II type 1 receptor (AT₁-R) and the angiotensin II type 2 receptor (AT₂-R). Thus, the AT₂-R gene may be involved in hypertension. Accordingly, our objective was to examine whether polymorphisms of the AT₂-R gene are involved in hypertension. The entire AT₂-R gene including the promoter region was screened to find polymorphisms. As a result, two novel single nucleotide polymorphisms (SNPs), A1818T in intron 2 and G4303A in exon 3, as well as two known SNPs, A1675G in intron 1 and C4599A in exon 3, were identified. These four SNPs had similar allele frequencies, and the A1675G and C4599A polymorphisms were in almost complete linkage disequilibrium. Because the AT₂-R gene is located on the X chromosome, we analyzed the possible association between the C4599A polymorphism and hypertension in men and in women separately in two large Japanese populations. This analysis showed that the C4599A polymorphism was associated with hypertension in women (p =0.0058), but not in men. Moreover, this female-specific association was pronounced in premenopausal women. The female-specific association may be helpful in conducting further molecular and biological studies on the relationship among sex, the renin-angiotensin system, and hypertension. (Hypertens Res 2003; 26: 547-552)

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Haplotype Analysis of the Prostacyclin Synthase Gene and Essential Hypertension

Tomohiro NAKAYAMA, Masayoshi SOMA, Akira HAKETA, Noriko AOI, Kotoko KO ...

Article type: Original Article
Subject area: Clinical studies
2003 Volume 26 Issue 7 Pages 553-557
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.553

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Previously, we discovered 3 polymorphisms in the prostacyclin synthase (PGIS) gene: 1) T-192G, in the 5′-flanking region, a novel single-nucleotide polymorphism (SNP) that is not associated with essential hypertension (EH); 2) a variable number of tandem repeat (VNTR) polymorphism, 6 nucleotides upstream from the ATG start codon, that is associated with risk of cerebral infarction; and 3) C1117A, in exon 8, an SNP that does not cause an amino acid change in codon 373, and that is associated with risk of myocardial infarction (MI). The purpose of the present study was to establish haplotypes of the PGIS gene consisting of these 3 polymorphisms, and to assess the association between these haplotypes and EH. We detected 19 haplotypes. There was no significant difference in the overall distribution of haplotypes between EH and normotensive subjects. To summarize, we successfully identified haplotypes of the PGIS gene, and these haplotypes were not associated with EH. (Hypertens Res 2003; 26: 553-557)

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Experimental studies

Chronological Changes of α-Adrenoceptor-Mediated Vascular Constriction in Otsuka-Long-Evans-Tokushima Fatty Rats

Yasumasa YOSHIDA, Mitsumasa OHYANAGI, Tadaaki IWASAKI

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 7 Pages 559-567
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.559

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In recent years, it has been suggested that many factors are involved in the development of hypertension accompanying insulin resistance. Because changes in vascular reactivity could be one of these factors, we here investigated chronological changes of α-adrenoceptor (AR)-mediated peripheral arteriolar vasoconstriction in a rat model of type II diabetes. Otsuka-Long-Evans-Tokushima fatty (OLETF) rats that naturally develop insulin resistance at the age of 16 weeks and type II diabetes at the age of 30 weeks (DM group) and control rats (N group) were used. Arterioles with a diameter of approximately 100μm were removed from the cremaster muscle of 8-, 16- and 40-week-old rats and their diameters were measured in a tissue bath. The concentration-response curve (CRC) was determined for phenylephrine and UK14, 304 both with and without N^G-monomethyl-L-arginine (LNMMA). Although there were no significant differences in the CRC for phenylephrine between the 8-week-old DM group and N group, a leftward shift was seen for the 16- and 40-week-old DM groups. There were no significant differences in the CRC for UK14, 304 between the two groups at any age, but in the presence of LNMMA, a leftward shift was seen in the 8- and 16-week-old but not in the 40-week-old DM groups. One possible explanation for these results is that impaired endothelium-dependent dilatation may have offset the reduction in arteriolar smooth muscle contraction. In conclusion, in the OLETF rats, the sensitivity of α₁-AR-mediated arteriolar vasoconstriction increased after the onset of insulin resistance. The sensitivity of α₂-AR-mediated arteriolar smooth muscle contraction and endothelium-dependent vascular relaxation were both presumed to be impaired after the onset of type II diabetes. (Hypertens Res 2003; 26: 559-567)

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Effects of Benidipine and Candesartan on Kidney and Vascular Function in Hypertensive Dahl Rats

Kozo YAO, Hitoshi SATO, Rie SONODA, Yasuhiro INA, Kazuo SUZUKI, Tetsuj ...

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 7 Pages 569-576
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.569

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We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine, the angiotensin II type 1 receptor blocker (ARB) candesartan, and the combination of these drugs on blood pressure and kidney and vascular function in rats with salt-induced hypertension. Dahl salt-sensitive (DS) rats were fed with a high-salt (8% NaCl) diet from 7 weeks of age. Benidipine (1, 3 mg/kg), candesartan (1, 3 mg/kg), benidipine (3 mg/kg) combined with candesartan (3 mg/kg), or vehicle was administered orally after the start of the feeding. Relaxant responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) were measured to examine the vascular function. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by glomerular sclerosis and an increase in urinary albumin excretion. Relaxant responses to acetylcholine and sodium nitroprusside were impaired in superior mesenteric arterial rings from the hypertensive DS rats. SBP was significantly lower in all of the drug-treated groups than in the vehicle-treated group. The antihypertensive effect of benidipine at 3 mg/kg was more potent than that of candesartan at 3 mg/kg. The albuminuria was significantly decreased in the benidipine and benidipine plus candesartan groups, but not in the candesartan group. The level of SBP in the benidipine plus candesartan group was lower than that by either drug alone. In addition, benidipine alone and benidipine plus candesartan inhibited the glomerular sclerosis and the impairment of relaxant responses in the arteries. These results demonstrate that benidipine is more effective than candesartan in lowering blood pressure and preventing the impairment of kidney and vascular function in salt-sensitive hypertensive rats. In addition, the results suggest that combination therapy with benidipine and an ARB decreases blood pressure more effectively than either drug alone and may be useful for the treatment of hypertension. (Hypertens Res 2003; 26: 569-576)

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Effects of Uroguanylin, an Intestinal Natriuretic Peptide, on Tubuloglomerular Feedback

Tao WANG, Masahiko KAWABATA, Manabu HANEDA, Toshikazu TAKABATAKE

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 7 Pages 577-582
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.577

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Uroguanylin is an endogenous peptide that stimulates cyclic guanosine monophosphate (cGMP) production via the activation of guanylate cyclase C (GC-C) in the intestine and kidney. A high salt diet, but not intravenous salt load, enhances the secretion of biologically active uroguanylin from the intestine and increases its concentration in plasma and urine. Our purpose is to clarify the effect of uroguanylin on renal microcirculation and the tubuloglomerular feedback (TGF) mechanism. Clearance and micropuncture experiments were performed in anesthetized rats. TGF responsiveness was assessed in superficial nephrons by measuring the changes of early proximal flow rate (EPFR) in response to orthograde loop perfusion at 40 nl/min with artificial tubular fluid (ATF). Reductions in EPFR induced by loop perfusion during intravenous infusion of uroguanylin at the rate of 10 and 50 nmol/kg/h were similar yet significantly less than that during the control period (33±3% and 35±3% vs. 47±3%, p <0.05). Intraluminal application of uroguanylin at 10^-7 and 10^-5mol/l in ATF decreased EPFR by 40±3% and 33±7%, respectively, with the latter value being significantly less than the control (p <0.05). Intravenous infusion of uroguanylin did not significantly change whole kidney function. Administration of atrial natriuretic peptide (ANP), which activates GC-A and B, significantly suppressed TGF-mediated EPFR reduction either intravenously (10 nmol/kg/h) or intraluminally (10^-5mol/l in ATF) (9±3% and 13±2% vs. 47±3% of the control, p <0.05). In conclusion, uroguanylin clearly suppresses TGF both through intravenous and intraluminal routes, although the effects on glomerular microcirculation and whole kidney function are far less than those of ANP. (Hypertens Res 2003; 26: 577-582)

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Sodium Load Increases Renal Angiotensin Type 1 Receptors and Decreases Bradykinin Type 2 Receptors

Pia STEWEN, Eero MERVAALA, Heikki KARPPANEN, Tuulikki NYMAN, Outi SAIJ ...

Article type: Original Article
Subject area: Experimental studies
2003 Volume 26 Issue 7 Pages 583-589
Published: 2003
Released on J-STAGE: January 31, 2004

DOIhttps://doi.org/10.1291/hypres.26.583

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The regulation of both angiotensin receptors and bradykinin receptors during sodium intake is poorly understood. We hypothesized that an altered balance between renal angiotensin type 1 (AT₁) receptors and bradykinin type 2 (B₂) receptors might contribute to an increase in blood pressure during periods of high-sodium intake. We studied the effects of high-sodium intake on renal AT₁ receptors and B₂ receptors in 5-6-week-old spontaneously hypertensive rats (SHR) receiving high-sodium chloride (6% NaCl) or mineral salts (10.5%, composition: 57% NaCl, 28% KCl, 12% MgSO₄) compared to those receiving a low-sodium (NaCl 0.125%) diet for 10 weeks. Mineral salt intake was included due to its beneficial effects on blood pressure and cardiac hypertrophy. Receptor densities were measured by quantitative autoradiography. AT₁ receptors were quantified using incubation with ¹²⁵I-Sar¹-Ile⁸-angiotensin II and displacement was measured with PD123319 (10μmol/l), whereas B₂ receptors were quantified using ¹²⁵I-HPP-icatibant and displacement was measured with icatibant (3μmol/l). Compared to the SHR controls, a further increase in blood pressure occurred after 2 weeks in the 6% NaCl group and after 6 weeks in the mineral salt group. AT₁ receptor density increased in the renal cortex by 41% (p <0.01) in the 6% NaCl group and by 26% (p <0.05) in the mineral salt group. B₂ receptor density decreased in the renal medulla by 26% (p <0.01) in the 6% NaCl group, and decreased even more i.e., by 45% (p <0.001), in the mineral salt group. It was shown that a 6% NaCl or a 10.5% mineral salt loading was capable of increasing renal AT₁ receptor density and decreasing renal B₂ receptor density. An altered balance between these receptors might be associated with hypertension under conditions of sodium loading. (Hypertens Res 2003; 26: 583-589)

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