Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity.
OBJECTIVE
Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235 --> threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II.


METHODS
Hypertensive (n = 34, all off medication) and normotensive (n = 57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3 ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration.


RESULTS
After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P = 0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P = 0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response.


CONCLUSIONS
Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension.
Hopkins
P N
PN
Cardiovascular Genetics, Cardiology Division, University of Utah, Salt Lake City, USA.
Lifton
R P
RP
Hollenberg
N K
NK
Jeunemaitre
X
X
Hallouin
M C
MC
Skuppin
J
J
Williams
C S
CS
Dluhy
R G
RG
Lalouel
J M
JM
Williams
R R
RR
Williams
G H
GH
D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage*; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015345:Oligonucleotide Probes / Q000737:chemistry; D010375:Pedigree; D012077:Renal Artery / Q000502:physiology; D017595:Renal Plasma Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
D015345:Oligonucleotide Probes; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II