Physiological interaction between alpha-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure regulation.
The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for alpha-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling (P=0.009) and acute BP response to a saline infusion (P=0.021), BP lowering after thiazide treatment (P=0.008), and nocturnal systolic BP (P=0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides.
Manunta
Paolo
P
Division of Nephrology, Dialysis, and Hypertension, University "Vita-Salute" San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy. manunta.paolo@hsr.it
Lavery
Gail
G
Lanzani
Chiara
C
Braund
Peter S
PS
Simonini
Marco
M
Bodycote
Claire
C
Zagato
Laura
L
Delli Carpini
Simona
S
Tantardini
Cristina
C
Brioni
Elena
E
Bianchi
Giuseppe
G
Samani
Nilesh J
NJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001692:Biological Transport; D001794:Blood Pressure / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D000075702:Nedd4 Ubiquitin Protein Ligases; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D044767:Ubiquitin-Protein Ligases; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins; C000618485:Nedd4L protein, human; C498743:WNK1 protein, human