Hypertension

Blood pressure must be tightly regulated to permit proper supply of oxygen and nutrients to all vital organs. Low blood pressure indicates insufficient supply of oxygen and nutrients. High blood pressure (hypertension) delivers excess nutrients that may damage blood vessels, kidney and other organs. In addition, hypertension increases the workload on the heart, leading to early development of congestive heart failure. High pressure on blood vessels can also cause their rupture, resulting in stroke if it happens in the brain.

The blood pressure is equal to the cardiac output (blood volume pumped by the heart per minute) times the systemic vascular resistance. The two factors are regulated by complex systems including renin-angiotensin-aldosterone system, baroreceptors, natriuretic peptides, kinin--kallikrein system, adrenergic receptor system, and others. However, the major pathway leading to hypertension is surprisingly simple. It turns out that salt plays the central role in the pathogenesis of hypertension. 

Major Pathway for Hypertension

When there is excess salt in the body, the blood volume increases, because the amount of water must increase to maintain plasma sodium concentration at a constant level. This is accomplished by two mechanisms: (1) Excess salt increases the osmolality of the body fluids, thereby stimulating the thirst center to make the person drink more water. (2) The increase in osmolality also causes the release of antidiuretic hormone, which makes the kidneys to reabsorb water before it is excreted as urine. Since the blood pressure is proportional to the cardiac output (and the blood volume), this explains why excess salt should increase the blood pressure.

In addition to the direct relationship with blood pressure, cardiac output can also affect blood pressure indirectly through "autoregulation". Higher cardiac output triggers autoregulation mechanism to constrict blood vessels all over the body. Increased vasoconstriction also raises blood pressure.

Kidney and Salt

The amount of salt in the body is mainly controlled by kidneys, which filter over 170 liters of plasma containing 23 moles of sodium daily. More than 99 percent of the filtered sodium are reabsorbed at four locations: (1) the proximal tubule of the nephron (by Na⁺/H⁺ exchange), (2) the thick ascending loop of Henle (by Na-K-2Cl cotransport), (3) the distal convoluted tubule (by Na-Cl cotransport), and (4) the cortical collecting tubule (by epithelial sodium channels) (Figure). Gene mutations that increase salt reabsorption will raise blood pressure.

The epithelial sodium channels at the last location are tightly regulated by the renin–angiotensin-aldosterone system. Renin is an enzyme that can convert angiotensinogen into angiotensin I. The latter can further be converted into angiotensin II by angiotensin converting enzyme (ACE). Angiotensin I is inactive but angiotensin II can stimulate the secretion of aldosterone, which then binds to the mineralocorticoid receptor, triggering a series of events that lead to the increase of epithelial sodium channel activity. When blood pressure or sodium level is low, renin is released to increase epithelial sodium channel activity, thereby increasing salt reabsorption.

Associated Genes

ADD1
Encodes a cytoskeleton protein, adducin, which is involved in sodium reabsorption.

AGT
Encodes angiotensinogen, which can be converted into angiotensin by renin.

AGTR1, AGTR2
Encode angiotensin II receptors.

CLCNKB
Encodes a chloride channel that is involved in sodium reabsorption. Mutation of this gene causes Bartter syndrome type 3.

CYP11B2
Encodes a cytochrome P450 enzyme that is involved in the synthesis of aldosterone.

EDN1
Encodes endothelin-1, a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells.

GCGR
Encodes a glucagon receptor, which is involved in sodium reabsorption.

GNB3
Encodes a G-protein b3 subunit. The G protein is involved in signal transduction but the detailed mechanism is not known.

HSD11B1
Encodes the enzyme 11 b hydroxysteroid dehydrogenase, which catalyzes the conversion of cortisol to cortisone. Like aldosterone, cortisol can also activate mineralocorticoid receptor, but cortisone cannot. Therefore, the enzyme can protect mineralocorticoid receptor from being activated by cortisol.

KCNJ1 (ROMK)
Encodes a potassium channel that is involved in sodium reabsorption. Mutation of this gene causes Bartter syndrome type 2.

SLC12A1 (NKCC2)
Encodes a Na-K-2Cl cotransporter. Mutation of this gene causes Bartter syndrome type 1.

SLC12A3
Encodes a  Na-Cl cotransporter. Mutation of this gene causes Gitelman syndrome.

SCNN1A,B,G
Encodes the epithelial sodium channel. Mutation of either SCNN1B or SCNN1G causes Liddle syndrome.

WNK4
Encodes a serine-threonine kinase which regulates the balance between sodium reabsorption and potassium secretion.

Review Articles:

Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases - Physiol. Rev., 2005.

Transcriptional Regulation of Renin - Hypertension, 2005.

Six Truisms Concerning ACE and the Renin-Angiotensin System Educed From the Genetic Analysis of Mice - Circulation Research, 2005.

Genetics of essential hypertension - Human Molecular Genetics, 2004.

Novel Mechanisms Responsible for Postmenopausal Hypertension - Hypertension, 2004.

Salt Intake, Endothelial Cell Signaling, and Progression of Kidney Disease - Hypertension, 2004.

Salt handling and hypertension - J. Clin. Invest., 2004.

Angiotensin II and Cell Cycle Regulation - Hypertension, 2004.

The b₁ subunit of the Ca²⁺-sensitive K⁺ channel protects against hypertension - J. Clin. Invest., 2004.

Hypertension: b testing - J. Clin. Invest., 2003.

Negative regulators of sodium transport in the kidney: Key factors in understanding salt-sensitive hypertension? - J. Clin. Invest., 2003.