Genes, Diets, & Hypertension...Role of Dietary Potassium in Salt-Sensitive Hypertension Dietary K...
Transcript of Genes, Diets, & Hypertension...Role of Dietary Potassium in Salt-Sensitive Hypertension Dietary K...
Chou-Long Huang, MD PhD
Genes, Diets, & Hypertension
% Hypertensives0 10 20 30 40
Ave
rage
Dai
ly N
aCl I
ntak
e (g
m) 30
20
10
Japanese(Northern Japan)
Japanese(Southern Japan)
Americans (Northern US)
Pacific IslandersAlaska Eskimos
Dahl, 1960
Relationship between salt intake and hypertension
Dietary sodium intake
BPSensitive
Resistant
Sensitivity to Salt-Induced Hypertension
Genetic &Environmental factors
Urine Blood
NaENaC
Epithelial Na Channel(ENaC) Na
NaBlood volume
AldosteroneMRSteroid Hormones:1. Sex hormones2. Mineralocorticoids3. Glucocorticoids
Mineralcorticoidreceptor (MR)
Cortisol CortisolCortisone11-βHSD2
11-βHydroxysteriod dehydrogenase
Defense Mechanisms Against Salt-Induced Hypertension
1. Aldosterone
Na intake Na reabsorption by kidney
Circulating volumeAldosterone
2. Pressure-Natriuresis
Na intake Na reabsorption by kidney
Circulating volumeBlood pressure
Dietary sodium intake
BPSensitive
Resistant
Sensitivity to Salt-Induced Hypertension
Genetic &Environmental factors
Urine Blood
NaENaC
AldosteroneMR
CortisolCortisone11-βHSD2
Cortisol
Liddle’sDisease
Genetic Factors (Diseases) That Increase Na Reabsorption
Liddle’s Disease
1. Autosomal-dominant disease featured by hypertension and hypokalemia (low blood potassium).
2. Occurs a result of gain-of-function mutations of ENaC, leading to increased number of ENaC channels at the cell surface
NaENaC
Normal
Blood
Na
Kidney
NaENaC
NaENaC
NaENaC
Liddle’s Disease
Hypertension
BloodKidney
Na
Na
Na
Patch-Clamp Recording of Ion Channels
Glass Pipette
NaCl
Cell with ENaC
NaCl
Suction NaCl
Na
Na
pico (10 ) Amp -12
Liddle’s Disease
NaENaC
Normal
Blood
Na
Kidney
NaENaC
NaENaC
NaENaC
Liddle’s Disease
Hypertension
BloodKidney
Na
Na
Na
Cell Membrane Proteins are Endocytosed and Degraded
Recognition of Proteins for Clathrin-Mediated Endocytosis
1. Intracellular region contains specific amino acid sequence forrecognition by AP2 or clathrin
NPXY (asparagine-proline-any-tyrosine)
2. Tagging mechanism: Ubiquitin (Ub) is a 76 amino acid peptide that can be used to tagproteins destined for endocytosis
UbNedd4-2
Nedd4-2 is a ubiquitin ligase. Nedd4-2 attachs ubiquitin (Ub) molecules to membrane proteins.
Nedd4-2 binds to intracellular region of proteinsrich in amino acid proline (P) and tyrosine (Y)
Ubiquitination of membrane proteins leads to their endocytosis and degradation.
Ub
ENaC
Mutations of ENaC in Liddle’s Disease Prevent Ubiquitination
PY
Urine Blood
NaENaC
AldosteroneMR
CortisolCortisone11-βHSD2
Cortisol
Liddle’sDisease
Conn’sDisease
AME (Apparent Mineralcorticoid
Excess)
X
Licorice
Genetic Factors (Diseases) That Increase Na Reabsorption
Apparent Mineralcorticoid Excess (AME)
1. Autosomal-recessive disease
2. Occurs as result of loss-of-function mutations of 11-βHSD2
Liddle’sDisease
Autosomal-dominantGain-of-function mutation
NaENaC
AldosteroneMR
CortisolCortisone11-βHSD2
Cortisol
AME (Apparent Mineralcorticoid
Excess)
X
In general, loss-of-function mutations are inherited as recessive
Exceptions:
1. Haplo-insufficiency (50% of protein function is insufficient)2. Second-hit phenomena (somatic mutation on top of inherited
recessive mutation3. Dominant-negative effect (mutant protein antagonizes
non-mutant protein function)
Dietary sodium intake
BPSensitive
Resistant
Sensitivity to Salt-Induced Hypertension
Genetic &Environmental factors
StressSmokeCocaine
Potassium deficiency
BP
Role of Dietary Potassium in Salt-Sensitive Hypertension
DietaryK Intake
Dietary sodium intake
Late paleolithic Current
Sodium (meq) ~20 ~150
Potassium (meq) ~320 ~50
Ratio 1:16 3:1
Dietary Sodium and Potassium Intake in Paleolithic vs Current Nutrition
Eaton and Konner, “Paleolithic Nutrition”, NEJM, 1985
Prevalence of Hypertension Inversely Related to Potassium Intake
Herbert Langford, in “Dietary potassium and hypertension: Epidemiologic data”. Annals. Int. Med, 1983. A low potassium intake can be considered an unindictedcoconspirator in hypertension.
Dietary potassium intake
Prev
alen
ce o
f HTN
(%)
Morris et a., Hypertension, 1999
High Dietary Potassium Intake Suppress Salt-Induced Hypertension
24 B, 14 W healthy normotensive subjects
15 meq 250 meqNa
K 30 meq 70 meq or 120 meq
Week 0 1 2 3 4 5 6
Genetic Diseases That Increase Na Reabsorption
NaENaC
AldosteroneMR
CortisolCortisone11-βHSD2
Cortisol
Liddle’s Disease:gain-of-function mutations of ENaC
AME: loss-of-function mutations of 11-βHSD2
X
Gordon’s syndrome: gain-of-function mutation of WNK1 kinase
WNK1
K
Low potassium intake
K
High potassium intake
ENaC
WNK1
ENaC Na
WNK1
Blood pressure
NaNaNa
Blood pressure
Dietary sodium intake
BPSensitive
Resistant
Mechanism of Salt-Induced Hypertension
Genetic &Environmental factors
StressSmokeCocaine
Potassium deficiency