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