WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.
Amino Acid Sequence ; Animals ; Cell Proliferation ; Cell Survival ; Humans ; Hyperkalemia/enzymology/etiology/genetics ; Hypertension/enzymology/etiology/genetics ; Kidney/enzymology ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neoplasms/enzymology/etiology/genetics ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/genetics/*metabolism ; Pseudohypoaldosteronism/enzymology/etiology/genetics ; Sequence Homology, Amino Acid ; Signal Transduction ; Syndrome

Renin-angiotensin system is considered important in the genesis of hypertension and development of end-stage renal disease (ESRD) in autosomal dominant polycystic kidney disease (ADPKD). The angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with susceptibility to the development of some renal diseases. We investigated the association of ACE gene polymorphism with the progression to hypertension and ESRD in 108 patients with ADPKD. The ACE I/D polymorphism was amplified with the flanking primers by polymerase chain reaction. In patients genotyped for ACE gene polymorphism, the frequencies of DD (15+ACU-), ID (51+ACU-) and II (34+ACU-) genotypes were similar to those of the general population. Of the 108 patients, 64 (59+ACU-) developed hypertension and 24 (22+ACU-) reached ESRD at the time of study. The prevalence of hypertension was not significantly different among the three genotypes. The mean renal survival time was 53-6 yr in II genotype, 5510 yr in ID genotype and 529 yr in DD genotype which was not significantly different among them. Cumulative renal survival was not significantly different either. There was no association of ACE gene polymorphism with the prevalence of hypertension and renal survival in ADPKD. We suggest that ACE I/D polymorphism is not an important modifying gene in the progression of ADPKD.
Adult ; Aged ; Comparative Study ; Disease Progression ; Female ; Genetic Predisposition to Disease ; Genotype ; Human ; Hypertension, Renal/etiology ; Hypertension, Renal/epidemiology ; Kidney Failure, Chronic/etiology ; Kidney Failure, Chronic/epidemiology ; Korea/epidemiology ; Male ; Middle Age ; Peptidyl-Dipeptidase A/genetics+ACo- ; Polycystic Kidney, Autosomal Dominant/genetics+ACo- ; Polycystic Kidney, Autosomal Dominant/epidemiology ; Polycystic Kidney, Autosomal Dominant/enzymology ; Polycystic Kidney, Autosomal Dominant/complications ; Polymerase Chain Reaction ; Polymorphism (Genetics)+ACo- ; Prevalence

Renin-angiotensin system is considered important in the genesis of hypertension and development of end-stage renal disease (ESRD) in autosomal dominant polycystic kidney disease (ADPKD). The angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with susceptibility to the development of some renal diseases. We investigated the association of ACE gene polymorphism with the progression to hypertension and ESRD in 108 patients with ADPKD. The ACE I/D polymorphism was amplified with the flanking primers by polymerase chain reaction. In patients genotyped for ACE gene polymorphism, the frequencies of DD (15+ACU-), ID (51+ACU-) and II (34+ACU-) genotypes were similar to those of the general population. Of the 108 patients, 64 (59+ACU-) developed hypertension and 24 (22+ACU-) reached ESRD at the time of study. The prevalence of hypertension was not significantly different among the three genotypes. The mean renal survival time was 53-6 yr in II genotype, 5510 yr in ID genotype and 529 yr in DD genotype which was not significantly different among them. Cumulative renal survival was not significantly different either. There was no association of ACE gene polymorphism with the prevalence of hypertension and renal survival in ADPKD. We suggest that ACE I/D polymorphism is not an important modifying gene in the progression of ADPKD.
Adult ; Aged ; Comparative Study ; Disease Progression ; Female ; Genetic Predisposition to Disease ; Genotype ; Human ; Hypertension, Renal/etiology ; Hypertension, Renal/epidemiology ; Kidney Failure, Chronic/etiology ; Kidney Failure, Chronic/epidemiology ; Korea/epidemiology ; Male ; Middle Age ; Peptidyl-Dipeptidase A/genetics+ACo- ; Polycystic Kidney, Autosomal Dominant/genetics+ACo- ; Polycystic Kidney, Autosomal Dominant/epidemiology ; Polycystic Kidney, Autosomal Dominant/enzymology ; Polycystic Kidney, Autosomal Dominant/complications ; Polymerase Chain Reaction ; Polymorphism (Genetics)+ACo- ; Prevalence

OBJECTIVETo determine whether polymorphism of NOS2A promoter -969G>C is associated with the portal hypertension of liver cirrhosis.

METHODSA case control study covering 106 patients with liver cirrhosis due to hepatitis B virus(HBV) in comparison with 108 controls was performed using PCR-restriction fragment length polymorphism. The NOS2A mRNA and protein expression in liver cirrhosis tissues were detected by reverse transcription-PCR and Western blot. The recombinant plasmids of NOS2A promoter luciferase reporter gene were constructed and were transfected transiently into HepG2 cells for analyzing the functional activity of the promoter.

RESULTSThe frequencies of the C allele and GC genotype at NOS2A promoter -969G>C were significantly higher in portal hypertension group (16.9%, 33.8%) than in control group(8.8%, 17.6%)(P<0.05), and positive correlation (r=0.18) and association (OR=2.42) were noted. There was no significant difference in frequency distribution between single liver cirrhosis group and control group(P>0.05). The expressions of NOS2A mRNA and protein in liver cirrhosis tissues were more increased in C allele carriers with liver cirrhosis than in G allele carriers with liver cirrhosis, which led to higher functional activity of the promoter. Multivariate logistic regression analysis revealed that NOS2A polymorphism at promoter -969G>C is an independent novel risk factor for the occurrence of portal hypertension in patients with liver cirrhosis.

CONCLUSIONThe polymorphism of NOS2A promoter -969(G>C) is associated with portal hypertension of liver cirrhosis, which results in functional activity increase of NOS2A promoter and is an independent risk factor for portal hypertension.

Adult ; Female ; Fibrosis ; complications ; enzymology ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Hypertension, Portal ; enzymology ; etiology ; genetics ; Male ; Middle Aged ; Nitric Oxide Synthase ; biosynthesis ; genetics ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; genetics ; RNA, Messenger ; biosynthesis ; genetics

OBJECTIVETo investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH in a genetically homogenous Mongolia rural population of China.

METHODSIndividuals (n=1099) were recruited from general population of Kezuohouqi Banner in Inner Mongolian Autonomous Region.

RESULTSThe association was found between ACE genotype DD plus ID and EH, with an interaction between ACE genotype DD plus ID and cigarette smoking in an additive model. Cigarette smoking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 7.10 to 1.16. Interaction between ACE genotype DD plus ID and alcohol drinking on EH appeared an additive model. Alcohol drinking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 1.66 to 1.09. BMI and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 6.15 to 2.49. Interactions between ACE genotype and WHR on EH showed a multiplicative model. In a short,there was an interaction between ACE gene and cigarette smoking, alcohol drinking and BMI on EH, especially in a low dose-exposure effect

CONCLUSIONIt is important for individuals who carry ACE D allele gene to prevent EH, and furthermore, to prevent and control coronary heart disease, in a view of population-based prevention.

Adult ; Age Factors ; Alcohol Drinking ; Anthropometry ; Blood Glucose ; China ; Cholesterol ; blood ; Cross-Sectional Studies ; Environmental Exposure ; Female ; Genetic Predisposition to Disease ; Humans ; Hypertension ; enzymology ; etiology ; genetics ; Male ; Middle Aged ; Mongolia ; ethnology ; Peptidyl-Dipeptidase A ; genetics ; Polymorphism, Genetic ; Renin-Angiotensin System ; genetics ; Risk Factors ; Rural Population ; Sex Factors ; Smoking ; Triglycerides ; blood