Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences.
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 FE(Li)+ 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 m(2), 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 approximately 45% of the variance in GFR response. Decline in FE(Li)+, 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.
O'Connor
D T
DT
Department of Medicine and Center for Molecular Genetics, University of California at San Diego, San Diego, CA92161, USA. doconnor@ucsd.edu
Tyrell
E A
EA
Kailasam
M T
MT
Miller
L M
LM
Martinez
J A
JA
Henry
R R
RR
Parmer
R J
RJ
Gabbai
F B
FB
D000328:Adult; D000596:Amino Acids / Q000097:blood / Q000652:urine; D001120:Arginine / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D005260:Female; D005819:Genetic Markers; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007678:Kidney Glomerulus / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000503:physiopathology; D016651:Lithium Carbonate; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D010641:Phenotype; D012307:Risk Factors; D015290:Second Messenger Systems
D000596:Amino Acids; D005819:Genetic Markers; D007328:Insulin; D009566:Nitrates; D009573:Nitrites; D016651:Lithium Carbonate; D001120:Arginine; D006152:Cyclic GMP