Genetic variations in the sodium balance-regulating genes ENaC, NEDD4L, NDFIP2 and USP2 influence blood pressure and hypertension.
OBJECTIVE
In humans, the kidneys regulate blood pressure by balancing sodium concentrations. Fine-tuning of renal sodium reabsorption and excretion depends on the epithelial sodium channel protein (ENaC: protein complex of SCNN1A, SCNN1B, and SCNN1G). The surface expression of ENaC components is directed by the ubiquitination of ENaC by NEDD4L, an ENaC-specific E3 ubiquitin ligase, and is regulated by the deubiquitination of ENaC by USP2. The activity of NEDD4L in turn is regulated by phosphorylation by SGK1 and also through interaction with NDFIP2.


METHODS
We analyzed 91 SNPs in 7 genes using the genotype data of 8,842 individuals from the Korea Association REsource subject pool for their correlation with blood pressure and hypertension.


RESULTS
25 SNPs in the SCNN1A, SCNN1B, SCNN1G, NEDD4L, NDFIP2, and USP2 loci were found to be associated with blood pressure. An additional hypertension case-control study identified 13 SNPs in SCNN1B, SCNN1G, and NEDD4L that were linked to hypertension.


CONCLUSIONS
These results support our hypothesis that individual variations in blood pressure are attributed to variants of the genes that regulate renal sodium reabsorption and excretion. Our data also suggest that it would be meaningful to investigate the role of NEDD4L-mediated ubiquitination in the pathogenesis of hypertension.
Jin
Hyun-Seok
HS
Department of Biomedical Engineering, School of Medicine, Kyung Hee University, Seoul, Korea.
Hong
Kyung-Won
KW
Lim
Ji-Eun
JE
Hwang
Sue-Yun
SY
Lee
Sang-Ho
SH
Shin
Chol
C
Park
Hun Kuk
HK
Oh
Bermseok
B
D000328:Adult; D000367:Age Factors; D000368:Aged; D001794:Blood Pressure / Q000235:genetics*; D016022:Case-Control Studies; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006977:Hypertension, Renal / Q000235:genetics* / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000075702:Nedd4 Ubiquitin Protein Ligases; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019655:Quantitative Trait, Heritable; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D000099184:Serum-Glucocorticoid Regulated Kinases
D010450:Endopeptidases; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C477747:NDFIP2 protein, human; C507045:SCNN1A protein, human; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human; C000618485:Nedd4L protein, human; C108665:USP2 protein, human