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

Utilization of the acute and chronically instrumented Sprague-Dawley rat model has provided new and informative data about the mechanisms of, and the role that circulating arginine vasopressin plays in, the regulation of blood flow to the renal medulla. Regional changes of blood flow were measured using implanted optical fibres and laser-Doppler flowmetry techniques. Transcriptional and translational sites of the V1a and V2 receptors were determined in microdissected intrarenal vascular segments from the cortex and medulla. Results from acute and chronic studies indicate the following. First, physiological elevations of plasma vasopressin concentration seen with 48 h of water restriction reduce blood flow to the inner medulla (via V1 receptors) while maintaining a constancy of blood flow to the outer medulla. Reduction of medullary blood flow is necessary to optimize urine osmolality during water restriction. Second, increases of plasma vasopressin concentration of as little as 8 pg ml(-1), which produce no change in baseline arterial pressure or renal cortical blood flow, can lower medullary blood flow selectively and greatly attenuate the arterial pressure-blood flow and pressure-natriuresis relationship. Third, medullary blood flow does not remain reduced in the face of sustained elevations of plasma vasopressin concentration, which appears to be related to the inability of vasopressin to produce a sustained hypertension. Fourth, V1a receptor mRNA and protein are present in the isolated cortical and medullary vasculature, but the V2 receptor mRNA and protein are found only in tubular segments. Levels of V2 receptor mRNA during water restriction were quantified using a competitive RT-PCR and a deletion mutant RNA transcript to control for the efficiency of the reaction, and Western blot analysis was utilized for quantification of the V2 receptor protein. The results demonstrated a time-dependent downregulation of the V2 receptor mRNA and protein within the rat kidney, specifically in the outer medulla. Fifth, the vasopressin-induced vasoconstriction of the medullary vasa recta microvessels was shown to be mediated via V1a receptors, and this response is normally modulated by vasopressin-stimulated release of nitric oxide (NO), via extravascular (presumably medullary collecting duct ) stimulation of V2 receptors. Finally, chronic vasopressin administration (10 days) increased nitric oxide synthase activity in the outer medulla and interstitial NO concentration in the medulla. These changes are essential to provide a constancy of blood flow to the renal medulla and buffer against the hypertensive actions of this potent vasoconstrictor peptide.
 ...
PMID:Control of the renal medullary circulation by vasopressin V1 and V2 receptors in the rat. 1079 26

Autosomal recessive polycystic kidney disease is a heritable but phenotypically variable disorder characterized by varying degrees of nonobstructive renal collecting duct ectasia, hepatic biliary duct ectasia and malformation, and fibrosis of both liver and kidneys. In the kidney, the dilated collecting ducts and interstitial fibrosis, when severe, may significantly impair renal function and result in hypertension and renal failure. Imaging typically shows large but reniform kidneys, diffusely increased renal parenchymal echogenicity at ultrasonography, and a striated nephrogram after contrast material administration. In the liver, periportal fibrosis accompanies the malformed and dilated bile ducts; this may result in portal hypertension. The liver may appear normal or may show intrahepatic biliary dilatation; once portal hypertension develops, splenomegaly and varices are usually evident. The relative degrees of kidney and liver involvement tend to be inverse: Children with severe renal disease usually have milder hepatic disease, and those with severe hepatic disease tend to evidence mild renal impairment. Presently, treatment consists of supportive management and control of hypertension. Replacement therapy for renal failure (dialysis or kidney transplantation) and control of portal hypertension (portal circulatory diversion or liver transplantation) may be necessary.
 ...
PMID:Autosomal recessive polycystic kidney disease: radiologic-pathologic correlation. 1083 31

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.
 ...
PMID:Prostaglandin E receptors and the kidney. 1089 84

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.
Hypertension 2000 Aug
PMID:CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity. 1094 76

Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.
 ...
PMID:Precancerous lesions in the kidney. 1114 93

Liddle's syndrome is a form of inherited hypertension linked to mutations in the genes encoding the epithelial Na+ channel (ENaC). These mutations alter or delete PY motifs involved in protein-protein interactions with a ubiquitin-protein ligase, Nedd4. Here we show that Na+ transporting cells, derived from mouse cortical collecting duct, express two Nedd4 proteins with different structural organization and characteristics of ENaC regulation: 1) the classical Nedd4 (herein referred to as Nedd4-1) containing one amino-terminal C2, three WW, and one HECT-ubiquitin protein ligase domain and 2) a novel Nedd4 protein (Nedd4-2), homologous to Xenopus Nedd4 and comprising four WW, one HECT, yet lacking a C2 domain. Nedd4-2, but not Nedd4-1, inhibits ENaC activity when coexpressed in Xenopus oocytes and this property correlates with the ability to bind to ENaC, as only Nedd4-2 coimmunoprecipitates with ENaC. Furthermore, this interaction depends on the presence of at least one PY motif in the ENaC complex and on WW domains 3 and 4 in Nedd4-2. Thus, these results suggest that the novel suppressor protein Nedd4-2 is the regulator of ENaC and hence a potential susceptibility gene for arterial hypertension.
 ...
PMID:A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. 1114 8

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.
 ...
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.
 ...
PMID:G protein-coupled prostanoid receptors and the kidney. 1118 68

The epithelial Na(+) channel (ENaC), which plays an essential role in renal Na(+) handling, is composed of three subunits (alpha beta gamma), each containing a conserved PY motif at the C terminus. In Liddle's syndrome, an inherited form of salt-sensitive hypertension, the PY motifs of either beta or gamma ENaC are deleted or modified. We have recently shown that a ubiquitin-protein ligase Nedd4 binds via its WW domains to these PY motifs on ENaC, that ENaC is regulated by ubiquitination, and that Xenopus laevis Nedd4 (xNedd4) controls the cell surface pool of ENaC when coexpressed in Xenopus oocytes. Interestingly, Na(+) transporting cells, derived from mouse cortical collecting duct, express two different Nedd4 isoforms, which we have termed mNedd4-1 and mNedd4-2. Only mNedd4-2, which is orthologous to xNedd4, but not mNedd4-1, is able to regulate ENaC activity, and this property correlates with the capability to bind to the ENaC complex. Hence, Nedd4-2 may be encoded by a novel susceptibility gene for arterial hypertension.
 ...
PMID:Liddle's syndrome: a novel mouse Nedd4 isoform regulates the activity of the epithelial Na(+) channel. 1147 28

Although it has been reported that the circulating adrenomedullin (AM) level is elevated in hypertension and renal failure, the pathophysiological significance of circulating and intrarenal AM in malignant hypertension remains unknown. We investigated the circulating and intrarenal AM system in rats with malignant hypertension by measuring the plasma level, renal tissue level, and mRNA abundance of AM and the mRNA abundance of AM receptor. We also investigated the effects of intravenously infused calcitonin gene-related peptide (CGRP)-(8-37), an antagonist of AM, on the hemodynamics and renal tubular function. We studied the following four groups: control Wistar-Kyoto rats (WKY), control spontaneously hypertensive rats (C-SHR), salt-loaded SHR (S-SHR), and DOCA-salt SHR (D-SHR). After 3 wk of DOCA treatment, D-SHR developed malignant hypertension. D-SHR were characterized by higher blood pressure, kidney weight, urinary protein excretion and blood urea nitrogen, and lower creatinine clearance compared with the other three groups. The plasma AM level and urinary excretion of AM were markedly higher in D-SHR than in the other three groups. In the kidney, the tissue AM level and the expression of AM mRNA in the renal medulla were significantly increased in D-SHR compared with the other three groups, whereas there were no significant differences in these levels in the renal cortex among the four groups. In the renal AM receptor system, the expression of the gene for receptor activity modifying protein 3 was significantly increased in the renal medulla in D-SHR compared with the other three groups. An immunohistochemical study revealed that AM immunostaining in renal collecting duct cells and distal tubules was more intense in D-SHR than in the other three groups. After CGRP-(8-37) infusion, blood pressure increased significantly and urinary sodium excretion and urine flow decreased significantly only in D-SHR. These results suggest that the increased circulating AM and renal AM and the increased expression of the mRNA for AM and its receptor may at least partly compensate for the malignant hypertensive state in certain forms of malignant hypertension via the hypotensive, natriuretic, and diuretic actions of AM.
 ...
PMID:Role of increased circulating and renal adrenomedullin in rats with malignant hypertension. 1170 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>