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Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks.

ABSTRACT: Blacks represent a high-risk population for salt-sensitive hypertension and heart disease, but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in blacks with hypertension and cardiac hypertrophy. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type (WT) or T555I/Q568P variant corin in the heart under the control of ?-myosin heavy chain promoter. The mice were crossed into a corin knockout (KO) background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of proatrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12 to 14 months of age when fed a normal salt diet or at a younger age when fed a high-salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in blacks who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in blacks.

SUBMITTER: Wang W

PROVIDER: S-EPMC3475733 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks.

Wang Wei W Cui Yujie Y Shen Jianzhong J Jiang Jingjing J Chen Shenghan S Peng Jianhao J Wu Qingyu Q

Hypertension (Dallas, Tex. : 1979) 20120917 5

Blacks represent a high-risk population for salt-sensitive hypertension and heart disease, but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in blacks with hypertension and cardiac hypertrophy. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were genera ...[more]

PMID: 22987923

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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

Project description:Background and objectivesHypertension is a common aging-related disorder. Salt intake is one of the main environmental factors contributing to the development of hypertension. Transgenic mice with one-half Klotho deficiency displayed a spontaneous BP increase and salt-sensitive hypertension in response to high sodium intake. Usually circulating levels of ?-Klotho decrease with age, and this reduction may be stronger in patients with several aging-related diseases. This study aimed at exploring the association of Klotho with salt sensitivity in humans.Design, setting, participants, & measurementsThe role of Klotho polymorphisms and ?-Klotho serum levels was evaluated in patients with hypertension who were treatment naive and underwent an acute salt-sensitivity test (discovery n=673, intravenous 2 L of 0.9% saline in 2 hours). Salt sensitivity was defined as a mean BP increase of >4 mm Hg at the end of the infusion. A total of 32 single nucleotide polymorphisms in the Klotho gene (KL), previously identified with a genome-wide association study, were used in the genetic analysis and studied for a pressure-natriuresis relationship.ResultsOf the patients with hypertension, 35% were classified as salt sensitive. The most relevant polymorphism associated with pressure natriuresis was the common missense single nucleotide polymorphism rs9536314, and the GG and GT genotypes were more represented among patients who were salt sensitive (P=0.001). Those carrying the G allele showed a less steep pressure-natriuresis relationship, meaning that a significant increase in mean BP was needed to excrete the same quantity of salt compared with patients who were salt resistant. KL rs9536314 also replicated the pressure-natriuresis association in an independent replication cohort (n=193) and in the combined analysis (n=866). There was an inverse relationship between circulating Klotho and mean BP changes after the saline infusion (r=-0.14, P=0.03). Moreover, circulating ?-Klotho was directly related to kidney function at baseline eGFR (r=0.22, P<0.001).ConclusionsKL rs9536314 is associated with salt-sensitive hypertension in patients with hypertension who are treatment naive. Moreover, circulating ?-Klotho levels were mainly related to diastolic BP changes at the end of a salt load and to eGFR as an expression of kidney aging.

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Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks.

Publications

Salt-sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks.

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