Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obstructive uropathy impairs nephron growth and function and is a major cause of end-stage renal disease in both adults and children. The major focus of this review article is to examine the evidence implicating a role for the kallikrein-kinin system in the pathophysiology of obstructive uropathy. Recent in vivo studies using specific kinin receptor antagonists and transgenic animals overexpressing or lacking various components of the kallikrein-kinin system have documented that kinins are involved in the regulation of renal function and blood pressure. Multiple roles have been proposed for kinins in obstructive uropathy. Renal kallikrein gene expression is suppressed in the kidney with chronic (>7 days) complete ureteral obstruction. In contrast, ureteral obstruction stimulates renin expression, creating a state of intrarenal angiotensin excess and kinin deficiency, which plays an important role in mediating the increased renal vascular resistance and decreased renal blood flow in the obstructed kidney. In addition to their hemodynamic effects, kallikrein and kinins influence tubular functions. For example, kallikrein influences urinary acidification in the distal nephron, suggesting that dysregulation of kallikrein expression may contribute to the acidification defect in the obstructed kidney. Also, kinins exert direct diuretic and natriuretic effects in the collecting duct and may be important in mediating the post-obstructive diuresis after the relief of urinary obstruction. The kinin substrate, kininogen, is a potent inhibitor of lysosomal cysteine proteases. Unlike kallikrein, kininogen synthesis is upregulated in the kidneys and liver of animals with urinary obstruction. By neutralizing cysteine proteases, kininogen may protect the tubular epithelium of obstructed nephrons from excessive apoptosis. The beneficial actions of kinins and kininogens on renal hemodynamics, tubular function, and cell survival suggest that strategies aimed at increasing intrarenal kinins, eg, ACE-kininase II inhibitors and kallikrein gene therapy, may represent a useful adjunct in the medical treatment of obstructive uropathy.
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PMID:The kininogen gene family in obstructive uropathy. 981 54

Renal cyclooxygenase-1 and cyclooxygenase-2 actively metabolize arachidonate to metabolism five primary prostanoids: prostaglandin E2, prostaglandin F2a, prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators interact with a family of distinct G-protein-coupled prostanoid receptors designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory effects on renal function. The intrarenal distribution of these prostanoid receptors has been mapped and the consequences their activation are being characterized. The FP, TP, and EP1 receptors preferentially couple to increased cell Ca2+. EP2, EP4, DP, and IP receptors stimulate cyclic adenosine monophosphate, whereas the EP3 receptor preferentially couples to Gi, inhibiting cyclic adenosine monophosphate generation. EP1 and EP3 messenger RNA expression predominate in the collecting duct and thick limb, respectively, where their stimulation reduces sodium chloride and water absorption, promoting natriuresis and diuresis. Interestingly, only a mild change in renal water handling is seen in the EP3 receptor knockout mouse. Although only low levels EP2 receptor messenger RNA are detected in kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor display salt-sensitive hypertension, suggesting it also plays an important role in salt excretion. In contrast, EP4 messenger RNA is readily detected in the glomerulus where it may contribute to the regulation of renin release and decrease glomerular resistance. TP receptors are also highly expressed in the glomerulus, where they may increase glomerular vascular resistance. The IP receptor messenger RNA is most highly expressed in the afferent arteriole and it may also modulate renal arterial resistance and renin release. At present there is little evidence for DP receptor expression in the kidney. Together these receptors act as physiologic buffers that protect the kidney from excessive functional changes during periods of physiologic stress. Loss of the combined effects of these receptors contributes to the side effects seen in the setting of nonsteroidal anti-inflammatory drug administration, whereas selective antagonists for these receptors may provide new therapeutic approaches in disease.
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PMID:Prostaglandin receptors: their role in regulating renal function. 1065 21

AVP not only increases osmotic water permeability (Pf) in the rat cortical collecting duct (CCD), but also acts synergistically with aldosterone to augment sodium reabsorption (JNa). These effects are inhibited by catecholamines via alpha2 adrenergic receptors, and by dopamine. We review here studies designed to determine the mechanism and receptor involved in dopamine action. The inhibitory effect of dopamine on Na+ and water transport was found to be reversible, and was not produced by agonists specific to D1A and D1B receptors. D2-type (D2, D3 or D4) receptors and activation of the GTP-binding protein Gi were implicated by the observation that dopamine had no inhibitory effect when JNa and Pf were stimulated by a cyclic AMP analogue plus isobutylmethylxanthine. The only dopaminergic antagonist that reversed the inhibitory effect of dopamine was clozapine, which is relatively D4-specific. We also found that dopamine or D1-specific agonists by themselves had no effect on cAMP production. However, dopamine inhibited the high rate of AVP-dependent cAMP production, and this effect of dopamine was reversed by clozapine but not other antagonists or by inhibitors of protein kinase C. The D4 receptor was observed in western blots of renal cortical proteins, and it was localized to the collecting duct by RT-PCR and immuno-histochemistry using a D4-specific antibody. These results show that at least a portion of the natriuretic effect of dopamine can be attributed to inhibition of AVP-dependent Na+ reabsorption by the CCD, and they introduce another signalling system as a candidate in the aetiology of low-renin, salt-dependent hypertension.
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PMID:The collecting duct, dopamine and vasopressin-dependent hypertension. 1069 7

Prostaglandin E(2) is a major renal cyclooxygenase metabolite of arachidonate and interacts with four G protein-coupled E-prostanoid receptors designated EP(1), EP(2), EP(3), and EP(4). Through these receptors, PGE(2) modulates renal hemodynamics and salt and water excretion. The intrarenal distribution and function of EP receptors have been partially characterized, and each receptor has a distinct role. EP(1) expression predominates in the collecting duct where it inhibits Na(+) absorption, contributing to natriuresis. The EP(2) receptor regulates vascular reactivity, and EP(2) receptor-knockout mice have salt-sensitive hypertension. The EP(3) receptor is also expressed in vessels as well as in the thick ascending limb and collecting duct, where it antagonizes vasopressin-stimulated salt and water transport. EP(4) mRNA is expressed in the glomerulus and collecting duct and may regulate glomerular tone and renal renin release. The capacity of PGE(2) to bidirectionally modulate vascular tone and epithelial transport via constrictor EP(1) and EP(3) receptors vs. dilator EP(2) and EP(4) receptors allows PGE(2) to serve as a buffer, preventing excessive responses to physiological perturbations.
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PMID:Prostaglandin E receptors and the kidney. 1089 84

The principal goals of treatment of the patient in heart failure are the relief of their symptoms and improvement in their prognosis. Of all antiheart failure drugs currently available, the diuretics are therapeutically superior in their efficacy in relieving clinical symptoms and signs. Whether administered intravenously or orally, all diuretics result in a substantial reduction in the raised pulmonary vascular pressures in combination with a small reduction in cardiac output. Diuretics stimulate release of renin with subsequent activation of the renin-angiotensin-aldosterone system, particularly if used in large doses, although their quantitative impact on the neuroendocrine profile at different stages of heart failure remains to be defined. In patients with mild heart failure, diuretics reduce plasma catecholamine concentrations, but their sympatholytic effects in more severe cases are unknown, as are their effects on the metabolically active tissues in these patients. Diuretic resistance can be circumvented by segmental nephron blockade with a combination of low-dose diuretics that simultaneously block sodium reabsorption in the proximal tubule, the loop of Henle, the distal tubule, and the collecting duct. Diuretics improve symptoms of breathlessness and signs of peripheral edema in patients with congestive heart failure in direct relationship to the induced diuresis. These benefits are frequently associated with a substantial improvement in patients' appreciation of quality of life and economic capacity. There are few adverse reactions to chronic diuretic therapy, but the serum electrolytes should be monitored for hypokalemia and hypomagnesemia. The impact of diuretics on prognosis of patients with congestive heart failure is unknown; however, diuretics have been a major ingredient of the therapies used in all the survival trials with vasodilators, angiotensin-converting enzyme inhibitors, and beta-blocking drugs. In addition to their clinical benefits, diuretics are the most cost-effective treatment of any single drug group currently available for the treatment of patients with congestive heart failure.
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PMID:Diuretic therapy in congestive heart failure. 1117 82

Low-renin hypertension is common and usually implies increased retention of sodium (Na(+)). In every case of known etiology, there is a mineralocorticoid-induced increase in number of epithelial Na(+) channels (ENaCs) in the collecting duct of the kidney, leading to a state of "hyperENaCactivity." In primary aldosteronism, a result of either an adrenal adenoma or bilateral adrenal hyperplasia, aldosterone itself mediates the increase in ENaC function. A severe form of low-renin hypertension in which a molecular mutation in ENaC prevents removal of the channel from the cell surface, known as Liddle's syndrome, results in increased net ENaC activity but, in this case, independently of an increase in aldosterone. Glucocorticoid remedial aldosteronism, an autosomal dominant form of primary aldosteronism, results from a "new" or chimeric gene for aldosterone synthase. Adrenocorticotropic hormone stimulates its expression as well as secretion of aldosterone. Apparent mineralocorticoid excess results from a molecular mutation that allows cortisol to bind to the mineralocorticoid receptor. Both glucocorticoid remedial aldosteronism and apparent mineralocorticoid excess result in an increase in the number of ENaCs. The question remains whether low-renin essential hypertension is related to an increase in ENaC activity. Low-renin hypertension is most common in black patients, who tend to have lower levels of aldosterone as well as renin, which are features that resemble those found in Liddle's syndrome. Preliminary findings suggest that black patients with low-renin hypertension who are resistant to standard antihypertensive therapy respond favorably to the addition of spironolactone, a mineralocorticoid receptor antagonist that reduces ENaC activity.
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PMID:Low-renin hypertension: more common than we think? 1117 96

Renal cyclooxygenase 1 and 2 activity produces five primary prostanoids: prostaglandin E2, prostaglandin F2alpha, prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators interact with a family of distinct G protein-coupled prostanoid receptors designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory effects on renal function. The intrarenal distribution of these prostanoid receptors has been mapped, and the consequences of their activation have been partially characterized. FP, TP, and EP1 receptors preferentially couple to an increase in cell calcium. EP2, EP4, DP, and IP receptors stimulate cyclic AMP, whereas the EP3 receptor preferentially couples to Gi, inhibiting cyclic AMP generation. EP1 and EP3 mRNA expression predominates in the collecting duct and thick limb, respectively, where their stimulation reduces NaCl and water absorption, promoting natriuresis and diuresis. The FP receptor is highly expressed in the distal convoluted tubule, where it may have a distinct effect on renal salt transport. Although only low levels of EP2 receptor mRNA are detected in the kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor exhibit salt-sensitive hypertension, suggesting that this receptor may also play an important role in salt excretion. In contrast, EP4 receptor mRNA is predominantly expressed in the glomerulus, where it may contribute to the regulation of glomerular hemodynamics and renin release. The IP receptor mRNA is highly expressed near the glomerulus, in the afferent arteriole, where it may also dilate renal arterioles and stimulate renin release. Conversely, TP receptors in the glomerulus may counteract the effects of these dilator prostanoids and increase glomerular resistance. At present there is little evidence for DP receptor expression in the kidney. These receptors act in a concerted fashion as physiological buffers, protecting the kidney from excessive functional changes during periods of physiological stress. Nonsteroidal anti-inflammatory drug (NSAID)-mediated cyclooxygenase inhibition results in the loss of these combined effects, which contributes to their renal effects. Selective prostanoid receptor antagonists may provide new therapeutic approaches for specific disease states.
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PMID:G protein-coupled prostanoid receptors and the kidney. 1118 68

The interaction of ANG II with intrarenal AT1 receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2 receptors is unknown. The present studies determined the effect of early diabetes on components of the glomerular renin-angiotensin system and on expression of kidney AT2 receptors. Three groups of rats were studied after 2 wk: 1) control (C), 2) streptozotocin (STZ)-induced diabetic (D), and 3) STZ-induced diabetic with insulin implant (D+I), to maintain normoglycemia. By competitive RT-PCR, early diabetes had no significant effect on glomerular mRNA expression for renin, angiotensinogen, or angiotensin-converting enzyme (ACE). In isolated glomeruli, nonglycosylated (41-kDa) AT1 receptor protein expression (AT1A and AT1B) was increased in D rats, with no change in glycosylated (53-kDa) AT1 receptor protein or in AT1 receptor mRNA. By contrast, STZ diabetes caused a significant decrease in glomerular AT2 receptor protein expression (47.0 +/- 6.5% of C; P < 0.001; n = 6), with partial reversal in D+I rats. In normal rat kidney, AT2 receptor immunostaining was localized to glomerular endothelial cells and tubular epithelial cells in the cortex, interstitial, and tubular cells in the outer medulla, and inner medullary collecting duct cells. STZ diabetes caused a significant decrease in AT2 receptor immunostaining in all kidney regions, an effect partially reversed in D+I rats. In summary, early diabetes has no effect on glomerular mRNA expression for renin, angiotensinogen, or ACE. AT2 receptors are present in glomeruli and are downregulated in early diabetes, as are all kidney AT2 receptors. Our data suggest that alterations in the balance of kidney AT1 and AT2 receptor expression may contribute to ANG II-mediated glomerular injury in progressive diabetic nephropathy.
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PMID:Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. 1120 1

Bartter syndrome and Gitelman syndrome are primary hereditary diseases characterized by hypokaliemia, alkalosis, hypertrophy of the juxtaglomerular complex with secondary hyperaldoteronism and normal blood pressure. They result from molecular disorders leading to a defect of sodium reabsorption in respectively the Henle's loop and the distal convoluted tubule. Biological adaptations of downstream tubular segments, i.e. distal convoluted tubule and collecting duct, are responsible for hypokaliemia, alkalosis, renin-aldosterone activation, prostaglandins hypersecretion and dysregulation of the urinary excretion of calcium and magnesium, illustrating the close integration of the regulation of different solutes in the distal tubular structures.
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PMID:[Primary molecular changes and secondary biological problems in Bartter and Gitelman syndrome]. 1199 28

The kidney contains a renin-angiotensin system that appears to regulate systemic blood pressure. Angiotensin II (Ang II) has stimulatory effects on sodium transport in multiple nephron segments via binding to plasma membrane AT(1) receptors. In the proximal tubule, Ang II production is substantial. The stimulatory effect of Ang II on proximal sodium transport is enhanced by renal nerves, and is associated with internalization of apical and basolateral receptors. In the cortical collecting duct, AT(1) receptors stimulate transport through apical sodium channels, and in the inner medulla, urea transport is enhanced by Ang II, contributing to increased sodium and water reabsorption. AT(1) receptors may also be linked to increased expression of certain tubular sodium transporters. In contrast to the stimulatory effects of AT(1) receptors on sodium transport, AT(2) receptors expressed in the adult kidney are linked to increased urinary sodium excretion and decreased blood pressure. This suggests that renal tubular AT(1) receptor activation serves as a protective mechanism to increase sodium reabsorption and blood pressure when extracellular fluid volume is threatened, whereas AT(2) receptors dampen this response. The interplay between these two receptor pathways in the kidney could have significant effects on long-term blood pressure control.
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PMID:The role of angiotensin II-stimulated renal tubular transport in hypertension. 1264 17


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