Mutations in the Na-Cl cotransporter reduce blood pressure in humans

被引:143
作者
Cruz, DN
Simon, DB
Nelson-Williams, C
Farhi, A
Finberg, K
Burleson, L
Gill, JR
Lifton, RP
机构
[1] Yale Univ, Boyer Ctr Mol Med, Sch Med, Dept Med, New Haven, CT 06510 USA
[2] Yale Univ, Boyer Ctr Mol Med, Sch Med, Dept Genet, New Haven, CT 06510 USA
[3] NIH, Bethesda, MD 20892 USA
关键词
blood pressure; sodium; dietary; hypokalemia; human; diuretics; genetics;
D O I
10.1161/01.HYP.37.6.1458
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na+ than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.
引用
收藏
页码:1458 / 1464
页数:7
相关论文
共 12 条
[1]   POLYMORPHIC DNA REGION ADJACENT TO THE 5'-END OF THE HUMAN INSULIN GENE [J].
BELL, GI ;
KARAM, JH ;
RUTTER, WJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1981, 78 (09) :5759-5763
[2]  
Bettinelli A, 1998, J NEPHROL, V11, P61
[3]   Dietary salt reduction in hypertension - What is the evidence and why is it still controversial? [J].
Chrysant, GS ;
Bakir, S ;
Oparil, S .
PROGRESS IN CARDIOVASCULAR DISEASES, 1999, 42 (01) :23-38
[4]  
DEHEIDE LJM, 1991, NETH J MED, V39, P148
[5]   PRIMARY STRUCTURE AND FUNCTIONAL EXPRESSION OF A CDNA-ENCODING THE THIAZIDE-SENSITIVE, ELECTRONEUTRAL SODIUM-CHLORIDE COTRANSPORTER [J].
GAMBA, G ;
SALTZBERG, SN ;
LOMBARDI, M ;
MIYANOSHITA, A ;
LYTTON, J ;
HEDIGER, MA ;
BRENNER, BM ;
HEBERT, SC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (07) :2749-2753
[6]  
GAMBA G, 1994, J BIOL CHEM, V269, P17713
[7]   BLOOD-PRESSURE CONTROL - SPECIAL ROLE OF THE KIDNEYS AND BODY-FLUIDS [J].
GUYTON, AC .
SCIENCE, 1991, 252 (5014) :1813-1816
[8]   Molecular genetics of human blood pressure variation [J].
Lifton, RP .
SCIENCE, 1996, 272 (5262) :676-680
[9]   VARIANT OF BARTTERS-SYNDROME WITH A DISTAL TUBULAR RATHER THAN LOOP OF HENLE DEFECT [J].
PUSCHETT, JB ;
GREENBERG, A ;
MITRO, R ;
PIRAINO, B ;
WALLIA, R .
NEPHRON, 1988, 50 (03) :205-211
[10]   Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption [J].
Simon, DB ;
Lu, Y ;
Choate, KA ;
Velazquez, H ;
Al-Sabban, E ;
Praga, M ;
Casari, C ;
Bettinelli, A ;
Colussi, C ;
Rodriguez-Soriano, J ;
McCredie, D ;
Milford, D ;
Sanjad, S ;
Lifton, RP .
SCIENCE, 1999, 285 (5424) :103-106