Angiotensinogen genotype predicts abnormal renal hemodynamics in young hypertensive patients.
OBJECTIVE
In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype.


METHODS
Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril.


RESULTS
Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril.


CONCLUSIONS
The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Tejas V
TV
Patel
Gordon H
GH
Williams
Naomi Deirdre L
ND
Fisher
D000328:Adult; D000367:Age Factors; D000804:Angiotensin II / Q000008:administration & dosage; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics*; D002216:Captopril / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012079:Renal Circulation; D012084:Renin-Angiotensin System / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D000806:Angiotensin-Converting Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D002216:Captopril