FUNCTIONAL ANGIOTENSINOGEN -20C PROMOTER VARIANT IS ASSOCIATED WITH DIFFERENT RENAL TUBULAR SODIUM HANDLING IN NORMOTENSIVE AND HYPERTENSIVE MEN: PP.24.456

Abstract

Objectives: Angiotensinogen (AGT) gene is the most relevant in the genetics of human hypertension. Angiotensin II affects renal tubular sodium reabsorbtion at both proximal and distal tubular sites. The AGT -20C functional promoter variant is associated with higher AGT expression in human kidney medulla. To test whether A-20C variants are related to segmental tubular sodium handling, white male subjects participating in two follow-up examinations of the Olivetti Heart Study 8-years apart were genotyped and the results correlated with renal sodium handling evaluated by the clearance of exogenous lithium. Design and methods: Genotype analysis was performed in 407 subjects of which 230 normotensive and 177 hypertensive (≥ 140/90 mmHg). Clinical, anthropometric and biochemical analyses were performed at both visits. Results: Hypertensive men had significant higher BMI (P < 0.001), waist circumference (P < 0.001), total cholesterol (P < 0.001), LDL cholesterol (P < 0.01), triglycerides (P < 0.001) and glucose (P < 0.001) than normotensive men. The -20C allele frequencies were not different between normotensive and hypertensive subjects (28 vs. 25%). Among the normotensives, the −20C carriers had a lower sodium fractional excretion (NaFE) (P = 0.019), due to markedly elevated fractional distal sodium reabsorption (P = 0.001). This association was maintained after adjustment for age, BMI and SBP (P = 0.001) and was confirmed at the 8-year follow-up examination (P = 0.025). The association between the -20C variant and increased distal sodium reabsorption was not observed among hypertensive participants. Conclusions: The altered distal tubular sodium handling observed in normotensive −20C carriers may be related to higher AGT expression in kidney medulla induced by the −20C variant. The reason why the alteration was not apparent in hypertensive individuals is unclear but it might be speculated that the effect of the variant was masked by the increased adipose tissue AGT production associated with abdominal adiposity and overweight in the hypertensive population. In conclusion, the AGT -20C promoter variant is associated with a significant alteration of distal renal tubular sodium handling in normotensive men.