Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-07-12
2003-12-09
Falk, Anne-Marie (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023500
Reexamination Certificate
active
06660474
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to essential hypertension, and more particularly to the use of genetic markers in diagnostic and therapeutic approaches to this disease.
BACKGROUND OF THE INVENTION
Essential hypertension, or high blood pressure of unknown cause, is a disease that affects 25-30% of Caucasians in The United States. Left untreated, hypertension leads to heart disease, stroke, myocardial infarction, and end-stage kidney disease. Since hypertension patients do not generally feel sick, it is often undiagnosed and left untreated until end organ failure has begun. Thus hypertension is the leading cause of cardiovascular morbidity and mortality in humans. Many hypertensives are salt sensitive in that a high salt diet will cause an elevation in blood pressure or exacerbate an already elevated blood pressure. Finding a measure for the propensity to develop high blood pressure could have a significant impact on reducing cardiovascular disease.
It has been estimated that genetic factors account for 30-40% of blood pressure variability in humans (Ward, In
Hypertension: Pathophysiology, Diagnosis and Management
, Laragh J H. and Brenner B M eds., (Raven Press, Ltd., New York, N.Y.), 81-100 (1990).) However, other estimates have suggested that genetic heritability of hypertension may be as high as 80% with 40% accounted for by one major gene (Cavalli, et al. In
The Genetics of Human Population
, (WH Freeman Co., South San Francisco, Calif.) 534-536 (1971)). The single major gene could effect blood pressure to such a significant extent that it would dominate many other genes that play a minor role in blood pressure control.
The central role of the kidneys in the genesis and maintenance of hypertension has been well established. When normal kidneys are transplanted into hypertensive rats, their blood pressure is normalized. On the other hand, when kidneys from hypertensive rats are transplanted into normotensive rats, they develop hypertension. Thus hypertension seems to follow the kidneys. It is also known that most human genetic forms of hypertension are associated with enhanced reabsorption of sodium in the kidney. Although there are many hormonal systems that regulate renal sodium excretion and blood pressure, the renal paracrine function of dopamine is well established as an important mechanism in long-term blood pressure regulation. The increased avidity of the renal proximal tubule for sodium in hypertension may be caused by defective renal paracrine action of dopamine. Dopamine causes a decrease in sodium reabsorption. Thus a defect in the action of dopamine would lead to an increase in sodium reabsorption and hypertension.
Dopamine exerts its actions via a class of cell surface receptors that belong to the rhodopsin-like family of G protein coupled receptors; these receptors have in common 7 trans-membrane domains. The dopamine receptors in the CNS and some endocrine organs are grouped into two major classes, the D1-like and the D2-like receptors. In the kidney and other organs outside the CNS, the D1-like receptors have been called DA1 receptors while the D2-like receptors have been called DA2 receptors. These distinctions are probably no longer necessary since no dopamine receptor is expressed exclusively inside or outside the CNS. However, there is differential regulation of the D1 receptor in neural and renal tissue. The two exons of the D1 receptor gene are transcribed in neural tissue while only the second exon is transcribed in renal tissue. The differential expression of the short and long D1 transcript may be due to tissue-specific expression of an activator protein driving transcription from a promoter at the 5′ non-coding region of the D1 receptor gene. Each of the D2-like dopamine receptor subtypes has several isoforms. However, no particular isoform is specifically expressed in peripheral tissues. See, Jose et. al., Pharmac. Ther. 80:149-182 (1998).
Two D1-like receptors are expressed in mammals: the D1 and D5 receptors which are known as D1A and D1B in rodents, respectively. Two additional D1-like receptors, D1C and D1D, are expressed in non-mammalian species. The D1-like receptors are linked to stimulation of adenylyl cyclase. The D1A receptor also stimulates phospholipase C activity, but this is secondary to stimulation of adenylyl cyclase. There seems to be a D1-like receptor, that is, as yet uncloned, linked to phospholipase C (PLC), through a pertussis toxin insensitive G-protein, Gq, that is distinct from the D1 and D5 receptor (Jose et al., Pharmac. Ther 80:149-182 (1998)). Three D2-like receptors are expressed in mammals: the D2, D3, and D4 receptors. The D2-like receptors are linked to inhibition of adenylyl cyclase and Ca2+ channels. The D2-like receptors also stimulate K+ channels although the D2 and D3 receptors have been reported to decrease voltage dependent potassium current in NG108-15 cells. Both the D2 and D3 receptors present in presynaptic nerves may also serve to decrease the release of both dopamine and norepinephrine.
All the mammalian dopamine receptors, initially cloned from the brain, have been found to be expressed in the kidney and urinary tract. Dopamine receptor subtypes are differentially expressed along the renal vasculature, the glomerulus, and the renal tubule where they regulate renal hemodynamics and electrolyte and water transport as well as renin secretion. Exogenous dopamine, at low doses, decreases renal vascular resistance and increases renal blood flow but with variable effects on glomerular filtration rate. Additional renal effects include an increase in solute and water excretion caused by hemodynamic and tubular mechanisms. The ability of renal proximal tubules to produce dopamine and the presence of receptors in these tubules suggest that dopamine can act in an autocrine or paracrine fashion. Endogenous renal dopamine increases solute and water excretion by actions at several nephron segments (proximal tubule, medullary thick ascending limb of Henle (mTAL), cortical collecting duct (CCD)). The magnitude of the inhibitory effect of dopamine on each nephron segment is modest but the multiple sites of action along the nephron cause impressive increases in solute and water excretion. The renal effects of dopamine are most apparent under conditions of solute (e.g., sodium, phosphate) or protein load. D1-like receptors, probably of the D1 subtype, vasodilate the kidney, inhibit sodium transport in proximal tubules by inhibition of sodium/hydrogen exchanger activity at the luminal membrane and sodium/potassium ATPase activity at the basolateral membrane. D1-like receptors also decrease sodium transport in the mTAL and in the CCD. The major functional D1-like receptor in the kidney is the D1 receptor. Presynaptic D2-like receptors are also vasodilatory. Postsynaptic D2-like receptors, by themselves, stimulate renal proximal sodium transport and inhibit the action of vasopressin at the CCD. However, in concert with D1-like receptors, postsynaptic D2-like receptors may act synergistically to inhibit sodium transport in the renal proximal tubule. The major D2-like receptor in the proximal tubule is the D3 receptor while the major D2-like receptor in the CCD is the D4 receptor. The ability of postsynaptic D2-like receptors, probably of the D3 subtype, to inhibit renin secretion may counteract the stimulatory effect of D1-like receptors on renin secretion and contribute to their synergistic action to increase sodium excretion in sodium replete states (Jose et al., supra).
In conclusion, although many years of intensive effort have revealed much about the etiology of essential hypertension, a single major gene that controls blood pressure has not been found. Thus the discovery of a major gene associated with blood pressure regulation would be important for understanding the mechanisms causing essential hypertension and lead to important new diagnostics and therapeutics.
SUMMARY OF THE INVENTION
Kinases are enzymes that catalyze the addition of a phosphate group onto proteins. G protein
Felder Robin A.
Jose Pedro
Falk Anne-Marie
Felder Robin A.
Lerner David Littenberg Krumholz & Mentlik LLP
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