Efficacy and Safety Evaluation of the New Association on Fixed Dose of Olmesartan + Chlorthalidone, Produced by EMS S.A,in Arterial Hypertension Control

The purpose of this study is to evaluate the non-inferiority clinical efficacy of two different drug associations in the essential hypertension control.

开始日期2024-12-01

申办/合作机构

EMS SA (Brazil)

100 项与 NCC x AT1R 相关的临床结果

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100 项与 NCC x AT1R 相关的转化医学

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0 项与 NCC x AT1R 相关的专利（医药）

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项与 NCC x AT1R 相关的文献（医药）

2021-07-01·Hypertension1区 · 医学

Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity

1区 · 医学

Article

作者: Uchida, Shinichi ; Itakura, Astuo ; Kanasaki, Keizo ; Kumagai, Asako ; Sohara, Eisei ; Koya, Daisuke ; Iijima, Hiroshi ; Takeda, Satoru

COMT (Catechol-O-methyl transferase), an enzyme that metabolizes catechol, requires magnesium (Mg 2+ ) to maintain its activity. Low COMT activity causes insufficient 2-methoxyestradiol (2-ME), a biologically active metabolite from hydroxyestradiol, which leads to hypertensive disorders, including preeclampsia. Hypoestrogenism increases the risk of salt-sensitive hypertension (SSH). SSH and preeclampsia are risk factors for each other; however, the molecular mechanism of this interaction is unclear. We focused on the interactive effect of Mg 2+ insufficiency and genetic COMT deficiency on SSH using 2 strains of mice with genetically distinct COMT activity. In male mice, BL6 (C57BL/6J), a high-activity COMT strain, displayed unaltered blood pressure regardless of the Mg 2+ and salt levels in food; DBA (DBA/2J), a low-activity COMT strain, developed SSH under low Mg 2+ and high-salt conditions. COMT inhibition in C57BL/6J strain also induced SSH. Treatment with 2-ME ameliorated SSH in both models. The ATR1 (angiotensin II type 1 receptor)–STE20-SPAK (serine-proline alanine-rich kinase)–NCC (sodium chloride cotransporter) axis, molecules associated with sodium reabsorption in distal convoluted tubules, was activated in mice that developed SSH. In female DBA mice, ovariectomized mice displayed SSH under low Mg 2+ associated with activation of ATR1-SPAK-NCC axis; 2-ME inhibited all, whereas the blood pressure of sham mice was unaltered regardless of any intervention. Our findings revealed that Mg 2+ insufficiency exaggerated the low COMT activity and induced SSH via the ATR1-SPAK-NCC axis due to 2-ME insufficiency, suggesting a new pathophysiological role that links COMT/2-ME deficiency with hypertensive syndrome.

2020-10-01·Clinical Kidney Journal3区 · 医学

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies

3区 · 医学

ReviewOA

作者: Stefanidis, Ioannis ; Tziastoudi, Maria ; Zintzaras, Elias

AbstractDespite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.

2020-06-01·The FASEB Journal2区 · 生物学

Sorting nexin 1 loss results in increased oxidative stress and hypertension

2区 · 生物学

Article

作者: Zeng, Chunyu ; Wang, Xiaoyan ; Jose, Pedro A. ; Asico, Laureano D. ; Beitelshees, Amber L. ; Gums, John G. ; Cuevas, Santiago G. ; Felder, Robin A. ; Feranil, Jun B. ; Johnson, Julie A. ; Turner, Stephen T. ; Chapman, Arlene B. ; Jones, John E. ; Boerwinkle, Eric ; Cooper‐DeHoff, Rhonda M. ; Schwartz, Gary L. ; Weinman, Edward J. ; Yang, Jian ; Villar, Van Anthony M. ; Armando, Ines

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D₅ receptor (D₅ R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1^-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT₁ R), NADPH oxidase (NOX) subunits, D₅ R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1^-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D₅ R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D₅ R agonist-induced increase in cAMP production and decrease in Na⁺ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.