Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.
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PMID:Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. 1295 13

Volume and sodium excess is the predominant factor in the pathogenesis of hypertension in dialysis patients. However, except for anephric patients, the relationship between volume status, blood pressure, and hemodynamics is not straightforward, but may vary between subgroups of patients. In general, the sensitivity of blood pressure to changes in the volume/sodium status appears to be increased in patients with end-stage renal disease. The blood pressure response to changes in the sodium/volume status may be influenced by disturbances in the activity of and response to various neurohumoral mechanisms, such as the renin-angiotensin and sympathetic nervous systems, Na-K-ATP-ase inhibitors, and the nitric oxide system. Regarding these aspects, there might be a parallel with salt-sensitive (essential) hypertension. Preliminary data showed a beneficial effect of sodium removal beyond changes in the volume status. Also of interest is the fact that prolonging dialysis time may improve blood pressure control without clear changes in the fluid status. It is hypothesized that a reduction in exchangeable sodium, by increased diffusive transport of sodium, in combination with increased removal of vasopressor substances, might be partly responsible for the observed blood pressure changes during long dialysis times. In conclusion, sodium and volume overload and neurohumoral factors coincide in the pathogenesis of hypertension in dialysis patients. Nevertheless, their exact relationship has not yet been elucidated and deserves further study.
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PMID:Role of sodium and volume in the pathogenesis of hypertension in dialysis patients. Reflections on pathophysiological mechanisms. 1473 12

Unilateral renal ischemia for 40 min in rat results in increased fibronectin (FN) expression in proximal tubular cells. This study examines the role of 24 h of blood reperfusion and the role of the renin-angiotensin system (RAS) on these results. Rats were submitted to 40 min of unilateral renal ischemia followed by 24 h of blood reperfusion. Renal function was assayed by clearance measurement in metabolic cages. Intracellular ATP and calcium were determined in proximal tubules. The expression and abundance of FN were investigated by reverse transcription-polymerase chain reaction, ELISA and Western blot either in isolated proximal tubules or cortex homogenates from control, ischemic and ischemic with reperfusion rats. Matrix metalloproteases (MMPs) activity was also measured. Losartan effects on renal function and on the abundance of FN and the MMPs activity in cortical homogenates were also measured. The renal function remained altered after 24 h of reperfusion in untreated and losartan-treated ischemic rats. On the other hand, the abundance of FN is increased after reperfusion both in isolated proximal tubules and total cortex homogenates and the same pattern was observed in the MMPs activity. Twenty-four h of blood reperfusion presented FN-mRNA signals similar to control ones. Losartan pretreated-rats presented diminished FN abundance in homogenates of cortex tissue from ischemic rats with or without reperfusion. Similar results were observed in the MMPs-activity. These results suggest that angiotensin II acting via the AT1 receptor plays a role in the development of tubulointersticial fibrosis after ischemia-reperfusion by activation of intrarenal RAS from the injured kidney.
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PMID:Losartan reverses fibrotic changes in cortical renal tissue induced by ischemia or ischemia-reperfusion without changes in renal function. 1522 98

Macula densa cells couple renal haemodynamics, glomerular filtration and renin release with tubular fluid salt and water reabsorption. These cells detect changes in tubular fluid composition through a complex of intracellular signalling events that are mediated by membrane transport pathways. Increases in luminal fluid sodium chloride concentration result in alterations in cell sodium chloride concentration, cytosolic calcium, cell pH, basolateral membrane depolarization and cell volume. Macula densa signalling then involves the production and release of specific paracrine signalling molecules at their basolateral membrane. Upon moderate increases in luminal sodium chloride concentration macula densa cells release increasing amounts of ATP and decreasing amounts of prostaglandin E(2), thereby increasing afferent arteriolar tone and decreasing the release of renin from granular cells. On the other hand, further increases in luminal concentration stimulate the release of nitric oxide, which serve to prevent excessive tubuloglomerular feedback vasoconstriction. Paracrine signalling by the macula densa cells therefore controls juxtaglomerular function, renal vascular resistance and participates in the regulation of renin release.
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PMID:Current mechanisms of macula densa cell signalling. 1528 59

Heart failure represents the composite endpoint of various cardiovascular disorders. Advanced pharmacotherapy resulted in significant improvement of overall survival, however with highly variable outcome, possibly due to genetic modification of drug disposition and action. This review highlights the role of genetic polymorphisms in systems responsible for disposition of drugs, used in heart failure patients (e.g. the polymorphic drug metabolizing enzymes such as cytochrome P450 enzymes, as well as polymorphic ATP-membrane transporters like P-glycoprotein (P-gp)). In addition, genetic variants in physiological systems, being target of drug action, particularly beta-adrenergic receptors, the renin-angiotensin-aldosterone system (RAAS)- and endothelin system, and the endothelial nitrogene monoxide (NO) synthase are reviewed. The current situation in pharmacogenomics of heart failure with respect to drug disposition and action is characterized by multiple studies investigating single components of a complex system. Therefore, overall conclusions regarding treatment and/or outcome of heart failure patients based on individual genetic traits require large prospective trials allowing for simultaneous assessment of multiple genetic variants in different systems. Using advanced screening technologies, such trials can be carried out in the near future.
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PMID:Pharmacogenomics of heart failure -- focus on drug disposition and action. 1536 11

The Na,K-ATPase transports three sodium ions out of the cell and two potassium ions into the cell using ATP hydrolysis for energy. The ion gradient formed by the Na,K-ATPase contributes to the resting membrane potential, maintains cellular excitability and is important for glucose and amino acid uptake in the cell. The alpha1 catalytic isoform is expressed in virtually all cell types. We have previously examined cardiac physiology of mice lacking one copy of the alpha1 isoform gene of the Na,K-ATPase. The observation of reduced cardiac contractility in the alpha1 heterozygous mice was unexpected since mice heterozygous for the alpha2 isoform displayed enhanced cardiac contractility similar to what would be observed with cardiac glycoside treatment. We further examined hearts from alpha1 heterozygous mice to identify genomic responses to reduced Na,K-ATPase capacity. Using microarray analyses, we identified groups of genes whose expressions were perturbed in the alpha1 heterozygous hearts compared to wild-type. Known functional relationships of these genes suggest that multiple biological pathways are altered by alpha1 hemizygosity including activation of the renin-angiotensin system, changes in genes of energy metabolism and transport and elevated brain natriuretic peptide. This suggests that Na,K-ATPase alpha1 isoform activity may be required in numerous cellular processes.
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PMID:Genetic profiling reveals global changes in multiple biological pathways in the hearts of Na, K-ATPase alpha 1 isoform haploinsufficient mice. 1570 99

Low-affinity state beta1-adrenoceptor (beta1-AR) was functionally expressed in some blood vessels and was different from beta1, beta2 and beta3-AR. In rat aorta, low-affinity state beta1-AR activation produced an endothelium-independent relaxation which was impaired in spontaneously hypertensive rats (SHRs). In the present work, we investigated whether renin-angiotensin system was involved in this alteration by evaluating the effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor or losartan, an AT1 angiotensin receptor antagonist. Cumulative concentration-response curves to low-affinity state beta1-AR agonists (CGP 12177, cyanopindolol or alprenolol) and to NS 1619, a large conductance Ca2+-activated K+ channels (BK) agonist were performed in denuded aortic rings isolated from control or treated Wistar Kyoto (WKY) rats or SHRs in different experimental conditions. The low-affinity state beta1-AR-mediated aortic vasodilation was impaired in 5 and 12 weeks old SHRs when compared to age-matched WKY. Twelve days enalapril (5 mg/kg/day) or losartan (15 mg/kg/day) treatments reduced systolic blood pressure (SBP) only in 12 weeks old SHRs whereas no significant change was observed in other groups. These treatments improved low-affinity state beta1-AR effect only in SHRs groups. In 12 weeks old WKY rats, CGP 12177-induced relaxation was insensitive to glibenclamide, a K(ATP)+ channel blocker, but was reduced by TEA or iberiotoxin, two large conductance Ca2+-activated K+ channel (BK) blockers. The impairment of NS 1619-induced vasodilation in both 5 and 12 weeks old SHRs was restored by enalapril or losartan. These results suggested that improvement of the low-affinity state beta1-AR-mediated vasodilation in 5 and 12 weeks old SHRs could be attributed to enhanced BK channels-induced hyperpolarization in SHRs independently of lowering of SBP.
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PMID:Low-affinity state beta1-adrenoceptor-induced vasodilation in SHR. 1604 86

ATP release from macula densa (MD) cells into the interstitium of the juxtaglomerular (JG) apparatus (JGA) is an integral component of the tubuloglomerular feedback (TGF) mechanism that controls the glomerular filtration rate. Because the cells of the JGA express a number of calcium-coupled purinergic receptors, these studies tested the hypothesis that TGF activation triggers a calcium wave that spreads from the MD toward distant cells of the JGA and glomerulus. Ratiometric calcium imaging of in vitro microperfused isolated JGA-glomerulus complex dissected from rabbits was performed with fluo-4/fura red and confocal fluorescence microscopy. Activation of TGF by increasing tubular flow rate at the MD rapidly produced a significant elevation in intracellular Ca(2+) concentration ([Ca(2+)](i)) in extraglomerular mesangial cells (by 187.6 +/- 45.1 nM) and JG renin granular cells (by 281.4 +/- 66.6 nM). Subsequently, cell-to-cell propagation of the calcium signal at a rate of 12.6 +/- 1.1 microm/s was observed upstream toward proximal segments of the afferent arteriole and adjacent glomeruli, as well as toward intraglomerular elements including the most distant podocytes (5.9 +/- 0.4 microm/s). The same calcium wave was observed in nonperfusing glomeruli, causing vasoconstriction and contractions of the glomerular tuft. Gap junction uncoupling, an ATP scavenger enzyme cocktail, and pharmacological inhibition of P(2) purinergic receptors, but not adenosine A(1) receptor blockade, abolished the changes in [Ca(2+)](i) and propagation of the calcium wave. These studies provided evidence that both gap junctional communication and extracellular ATP are integral components of the TGF calcium wave.
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PMID:Calcium wave of tubuloglomerular feedback. 1649 10

In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.
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PMID:Adenosine and kidney function. 1681 41

Renin binding protein (RnBP), a cellular renin inhibitor, was identified as an enzyme, GlcNAc 2-epimerase. Recombinant RnBP inhibited porcine renin activity in a dose dependent manner. However, the inhibition was neutralized by nucleotides, such as ATP, dATP, dGTP, dCTP or dTTP. Moreover, ATP inhibited the formation of hetero-complex of renin with RnBP, called high molecular weight (HMW) renin. On the other hand, N-ethylmaleimide (NEM), a SH-alkylating reagent inhibited the GlcNAc 2-epimerase activity concomitant with the decaying of the dimer to the monomer of the enzyme. The inhibition was modulated in the presence of ATP. These results indicate that nucleotides stabilize the dimeric form RnBP (GlcNAc 2-epimerase) and inhibited the formation of the renin-RnBP hetero complex, HMW renin.
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PMID:Effects of nucleotides on the interaction of renin with GlcNAc 2-epimerase (renin binding protein, RnBP). 1702 85


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