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Background: Hypertension is one of the major etiologies that cause chronic kidney disease (CKD) and can exacerbate kidney dysfunction. Zinc is an essential trace element playing a role in blood pressure regulation, and zinc deficiency, a common comorbidity in patients with CKD, can cause hypertension. However, the precise mechanism underlying zinc deficiency-induced hypertension is unknown. Sodium (Na + ) retention due to inappropriate Na + reabsorption in the renal tubule is the principal pathophysiology of hypertension. Therefore, this study aimed to investigate the association between zinc deficiency and salt sensitivity., Methods: Adult mice were fed a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet combined with/without high salt in drinking water (HS) for 4 weeks (n = 6 each). Changes in blood pressure, urinary sodium excretion, and the expressions of the proximal tubular Na + transporter, Na + /H + exchanger 3 (NHE3), which mostly contributes to filtered Na + reabsorption and the downstream Na + -Cl - transporter (NCC) were analyzed., Results: Urinary Na + excretion significantly increased in ZnD mice, indicating that zinc deficiency causes natriuresis. NHE3 expressions were significantly suppressed, whereas NCC was upregulated in ZnD mice. Interestingly, the combination of high salt and ZnD diet (HS-ZnD) reversed the urinary Na + loss. The NCC remained activated and NHE3 expressions paradoxically increased in HS-ZnD mice compared with those fed the combination of high salt and ZnA diet. In addition, blood pressure significantly increased only in HS-ZnD mice., Conclusion: The combination of zinc deficiency and high salt causes hypertension. Zinc is associated with salt-sensitivity, potentially through NHE3 and NCC regulation., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB)., Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine., Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication., Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.

Aim: Previous studies suggest that klotho gene polymorphisms may be associated with atherosclerosis, but did not assess the relationship between klotho gene polymorphisms and atherosclerosis parameters such as carotid artery intima-media thickness (IMT). Here, we studied whether klotho single nucleotide polymorphisms (SNP) were associated with carotid atherosclerosis., Methods: All subjects were Japanese. Eight-hundred and fifty-three patients with hypertension (465 men and 388 women) in the outpatient clinic and 1783 subjects from the general population (821 men and 962 women) attending health check-ups were analyzed in the present study. We measured mean IMT of the common carotid artery to evaluate carotid atherosclerosis. Four single nucleotide polymorphisms (SNP) (rs7323281; intron1, rs5644481; exon4, rs3752472; exon3, rs650439; intron4) of klotho were selected as representative SNP in haplotype blocks., Results: Multivariate logistic regression analysis adjusted by confounding factors showed a significant association of rs650439 with carotid atherosclerosis in hypertensive patients (TT vs TA vs AA, P < 0.01; TT + TA vs AA, P < 0.01). By ancova considering confounding factors, rs650439 was also significantly associated with mean IMT (TT + TA vs AA, P = 0.04) in the hypertensive population. However, there was no significant association between klotho SNP and carotid IMT in the general population. Compared to the general population, the subject group with hypertensive patients clearly had more atherosclerosis risk factors., Conclusion: Only in hypertensive patients was klotho rs650439 strongly associated with mean IMT thickening of the common carotid artery. Therefore, klotho SNP (rs650439) may influence on the progression of carotid atherosclerosis in patients with hypertension., (© 2010 Japan Geriatrics Society.)

CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P

Protein tyrosine kinase 2beta (PTK2B) is a member of the focal adhesion kinase family and is activated by angiotensin II through Ca2+-dependent pathways. An evidence exists that PTK2B is involved in cell growth, vascular contraction, inflammatory responses, and salt and water retention through activation of the angiotensin II type 1 receptor. To examine the contribution of PTK2B, we sequenced the PTK2B gene using 48 patients with hypertension, identified 62 genetic polymorphisms, and genotyped six representative single nucleotide polymorphisms in population-based case-control samples from 3655 Japanese individuals (1520 patients with hypertension and 2135 controls). Multivariate logistic regression analysis after adjustments for age, body mass index, present illness (hyperlipidemia and diabetes mellitus), and lifestyle (smoking and drinking) showed -22A>G to have an association with hypertension in men (AA vs. AG+GG: odds ratio=1.27; 95% confidence interval: 1.02-1.57; P=0.030). Another polymorphism, 53484A>C (K838T), in linkage disequilibrium with -22A>G showed a marginal association with hypertension in men (AA vs. AC+CC: odds ratio=1.25; 95% confidence interval: 0.99-1.57; P=0.059). Diastolic blood pressure was 1.6 mmHg higher in men with the AC+CC genotype of 53484A>C than those with the AA genotype (P=0.003), after adjustments for the same factors. These polymorphisms are in linkage disequilibrium with others in a range of 113 kb in PTK2B. The intracellular distribution of the recombinant PTK2B protein and that of the mutant protein with T838 were indistinguishable even after angiotensin II stimulation, both proteins localizing at a focal point in the peripheral area in the cells. Thus, a haplotype in PTK2B may play a role in essential hypertension in Japanese.

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Endothelin-1 (EDN1), a 21-amino acid peptide, is a potent vasoconstrictor with various pharmacological responses. EDN1 is synthesized from a 212-amino acid precursor protein, preproEDN1, through multiple proteolytic steps. Endothelin-converting enzyme (ECE) cleaves a Trp73-Val74 peptide bond in big-EDN1 to give rise to mature EDN1. In this study, we examined the possible association of genetic variations in ECE1 with hypertension in a general Japanese population and searched for missense mutations in and around the EDN1 polypeptide. We genotyped 5 single nucleotide polymorphisms (SNPs) in the ECE1 gene in 1,873 individuals from a general Japanese population and identified one SNP associated with hypertension in women (rs212528: TT vs. TC+CC: odds ratio=1.40; 95% confidence intervals: 1.04-1.89; p=0.026), after adjusting for confounding factors. The systolic blood pressure in women with the CC genotype was 6.44 mmHg higher than that in those with the TT genotype (p=0.007), after adjusting for the same factors. Next, to identify the missense mutations that may influence the biological activity of EDN1, we sequenced the genomic region that encodes EDN1 in 942 Japanese hypertensive patients. We identified a novel missense mutation, G36R, in one hypertensive patient, but no mutations were observed in EDN1. A gene polymorphism in EDN1, Lys198Asn, has been reported to be associated with hypertension in obese subjects. Taken together, these findings reveal that the EDN-ECE pathway is an important system involved in essential hypertension in Japanese.

Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n = 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese.

Background: Genome-wide scans from Italy and China suggest a hypertension-susceptible locus between D2S2278 (nucleotides 11,245,080 - 11,245,358) and D2S168 (nucleotides 11,467,214 - 11,467,422) on chromosome 2., Methods: We performed a large association study of polymorphisms in this region with blood pressure modulation in a Japanese general population. Forty-seven polymorphisms in 14 genes between nucleotide 8,845,292 and nucleotide 11,946,689, which contains D2S2278 and D2S168, were genotyped in 1880 individuals, 796 of whom were hypertensive and 1084 normotensive., Results: Multivariate logistic regression analysis with adjustment for age, body mass index, presence of hyperlipidemia, diabetes mellitus, and current smoking and drinking revealed that one single nucleotide polymorphism (SNP), IMS-JST126186, in HPCAL1 (hippocalcin-like 1) in women and two SNPs, IMS-JST149391 and IMS-JST149390, in GREB1 (gene regulated by estrogen in breast cancer 1) in men were significantly associated with both prevalence of hypertension and blood pressure levels. To examine the role of GREB1 in more detail, we identified 38 additional genetic variations in GREB1 by direct sequencing, and eight polymorphisms were genotyped. One SNP, 45718A>G, was significantly associated with hypertension and blood pressure level in men, and this SNP was in linkage disequilibrium with a SNP present at the 3' splice site of intron 11., Conclusion: Our study suggests that GREB1 and HPCAL1 are candidate hypertension-susceptibility genes in the Japanese general population and supports previous studies that also identified hypertension-related loci in this narrow region.