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.
Department of Medicine and Center for Molecular Genetics, University of California at San Diego, San Diego, CA92161, USA. doconnor@ucsd.edu
D T
DT
O'Connor
E A
EA
Tyrell
M T
MT
Kailasam
L M
LM
Miller
J A
JA
Martinez
R R
RR
Henry
R J
RJ
Parmer
F B
FB
Gabbai
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