(Hypertension. 2001;37:898.)
© 2001 American Heart Association, Inc.
Scientific Contribution |
Early Alteration in Glomerular Reserve in Humans at Genetic Risk of Essential Hypertension
Mechanisms and Consequences
Presented in abstract form at the Council for High Blood Pressure Research of the American Heart Association, Autumn 1998.
From the Department of Medicine and Center for Molecular Genetics, University of California at San Diego; and VA San Diego Healthcare System, San Diego, Calif.
Correspondence to Daniel T. O’Connor, MD, Department of Medicine and Center for Molecular Genetics, University of California, San Diego (9111H), 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail doconnor{at}ucsd.edu, Website http://medicine.ucsd.edu/hypertension
Essential
hypertension has a familial predisposition, but the phenotype
of elevated blood pressure has delayed penetrance. Because the kidney
is a crucial determinant of blood pressure homeostasis, we studied
early glomerular alterations in still-normotensive young
subjects at genetic risk of hypertension. Thirty-nine normotensive
adults (mean age 29 to 31 years), stratified by genetic risk (parental
family history [FH]) of hypertension (26 with positive FH [FH+], 13
with negative FH [FH-]), underwent intravenous infusion
of mixed amino acids. Before and during amino acid administration, we
measured glomerular filtration rate (GFR), putative second
messengers of amino acids (nitric oxide [NO·] metabolites and
cGMP), serum insulin and amino acid concentrations, and the
FELi+ as an index of renal proximal tubular
reabsorption. The FH+ group had a blunted GFR rise in response to amino
acids (2.43±8.16% versus 31.0±13.4% rise,
P=0.0126). The amino
acid–induced change in GFR correlated
(r=0.786,
P<0.01) with the change in
urinary NO· metabolite excretion; a diminished rise in urinary NO·
metabolite excretion in the FH+ group
(P=0.0105) suggested a
biochemical mechanism for the different GFR responses between FH
groups: a relative inability to convert arginine to NO·. The FH+
group had a far lower initial cGMP excretion at baseline (261±21.1
versus 579±84.9 nmol · h-1/1.73
m2,
P=0.001), although cGMP did not
change during the amino acid infusion
(P=0.703). FH status, baseline
GFR, and baseline serum insulin jointly predicted GFR response to amino
acids (P=0.0013), accounting
for 
45% of the variance in GFR response. Decline in
FELi+, an inverse index of proximal tubular
reabsorption, paralleled increase in GFR
(r=-0.506,
P=0.01), suggesting differences
in proximal tubular reabsorption during amino acids between the FH
groups. GFR response to amino acid infusion was blunted in the FH+
group despite significantly higher serum concentrations of 6 amino
acids (arginine, isoleucine, leucine, methionine,
phenylalanine, and valine) in the FH+ group, suggesting a novel form of
insulin resistance (to the amino acid–translocating action of insulin)
in FH+ subjects. We conclude that blunted glomerular
filtration reserve in response to amino acids is an early-penetrance
phenotype seen even in still-normotensive subjects at genetic
risk of hypertension and is linked to impaired formation of NO· in
the kidney. Corresponding changes in GFR and fractional excretion of
Li+ suggest that altered proximal tubular
reabsorption after amino acids is an early pathophysiologic mechanism.
Resistance to the amino acid–translocating actions of insulin may play
a role in the biological response to amino acids in this setting. This
glomerular reserve phenotype may be useful in
genetic studies of renal traits preceding or predisposing to
hypertension.
Key Words: hypertension, essential • genetics • glomerular filtration rate • kidney
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