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Adrenergic genetic mechanisms in hypertension and hypertensive kidney disease.

ABSTRACT: Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. In the tyrosine hyroxylase promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, 2 independent case-control studies (1,266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in the storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive kidney disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed such regulatory regions as the proximal promoter and 3'-UTR. In chromaffin cell-transfected CHGA 3'-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 3'-UTR displayed statistical associations with hypertension and hypertensive end stage renal disease. Therefore, I would like to review the common genetic variation in TH and CHGA as a cause of inter-individual variation in sympathetic activity, and ultimately blood pressure and hypertensive kidney disease.

SUBMITTER: Kang SW

PROVIDER: S-EPMC3741439 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Adrenergic genetic mechanisms in hypertension and hypertensive kidney disease.

Kang Sun Woo SW

Electrolyte & blood pressure : E & BP 20130630 1

Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. In the tyrosine hyroxylase promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, 2 independent ...[more]

PMID: 23946762

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Project description:BackgroundAnemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association.MethodsWe followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I(125) iothalamate) in place of eGFR.ResultsAt baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m(2). For example, the absolute decline in hematocrit per 10 mL/min/1.73 m(2) decline in longitudinal eGFR was -3.7, -1.3 and -0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m(2), respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m(2)). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR-hematocrit association did not differ by body mass index, serum albumin or C-reactive protein.ConclusionsMen, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m(2)) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit.

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Adrenergic genetic mechanisms in hypertension and hypertensive kidney disease.

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Adrenergic genetic mechanisms in hypertension and hypertensive kidney disease.

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