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)

Renal endothelin-1 (ET-1 ) production is increased by hypoxia and has been implicated in ischemia-induced renal hypoperfusion. Because the inner medullary collecting duct (IMCD) is a major source of ET- 1 in the kidney, and because ET- 1--in the setting of ischemic renal failure-may alter medullary perfusion, we sought to determine whether hypoxia modulated ET-1 production by IMCD cells. Primary cultures of rat IMCD cells were exposed to 21%, 3%, or 0%O2. IMCD ET-1 secretion significantly increased after exposure of cultures to 3% O2 (114.1% +/- 4.7% increase over control value) and 0%O2 (171.7% +/- 7.9% increase). ET-1 mRNA levels, as determined by reverse transcription-polymerase chain reaction, also increased 2.5-fold after 24-hour exposure to 0% O2. We speculate that a hypoxia-induced increase in IMCD ET-1 production plays a role in modulating renal medullary perfusion during ischemic renal failure.
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PMID:Hypoxia regulates endothelin-1 production by the inner medullary collecting duct. 945 26

The ability to control body hydration is frequently impaired with age. This mainly results from changes in thirst and from loss of renal concentrating ability. The cellular mechanisms responsible for this functional renal failure have been extensively studied in different experimental models. Although the loss of nephrons sometimes observed with age impairs the ability of the kidney to retain water, a similar defect was reported in animals free of glomerulosclerosis, indicating that the reduction in the number of nephrons was not the only cause. Because age-related polyuria has also been demonstrated in rats with unchanged secretion of vasopressin, renal changes in water reabsorption was hypothesized. Such alterations have been searched along the whole length of the nephron. Neither the single nephron filtration rate nor proximal or early distal flow rates were modified in senescent animals where water reabsorption in the collecting duct was reduced. The affinity and the density of the V2 receptors were mainly constant in most experimental models of ageing. In contrast, intracellular cAMP accumulation following vasopressin stimulation was reduced in the oldest animals. The expression of aquaporins in luminal and basolateral membranes of the collecting duct epithelial cells was altered. The amount of basolateral aquaporin 3 and 4 was respectively decreased by 50 per cent and unchanged in renal papilla. In addition, the expression of aquaporin 2, which is rate limiting for the osmotic permeability of the collecting duct, was reduced by 50 per cent in the outer medulla and by 80 per cent in the inner medulla of the senescent animals. This drop in aquaporin 2 expression in the distal part of the nephron could be the main cause for the fall in concentrating ability of the kidney and the age-related impaired control of hydration.
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PMID:[Kidney aging: cellular mechanisms of problems of hydration equilibrium]. 1021 38

The effects of hypercholesterolemia on ischemic renal failure were evaluated in rats subjected to 60 min of left renal artery clamping and contralateral nephrectomy. One group of rats (HC) was kept on a cholesterol-supplemented diet for 3 weeks before renal injury and compared to a group fed a regular diet (ND). Two days after renal ischemia, inulin clearance (C(in), ml/min per 100 g BW) was lower in HC-rats (0.033 +/- 0.011) than in ND-rats (0.227 +/- 0.037; P < 0.01). indicating that hypercholesterolemia potentiated renal ischemic injury. Twenty-one days after renal ischemia the C(in) of HC-rats did not differ from ND-rats, suggesting that hypercholesterolemia did not limit late recovery. Since nitric oxide production is impaired in HC, L-arginine (50 mg/kg BW i.v.) was administered immediately after ischemia. Two days after ischemia, L-arg did not protect ND-rats from ischemia, while the C(in) and renal blood flow were higher in L-arg-treated HC rats than in untreated HC rats (C(in) = 0.125 +/- 0.013 rats vs. 0.033 +/- 0.011; P < 0.001) (RBF = 3.96 +/- 0.64 vs. 2.40 +/- 0.20 ml/min per 100 g BW; P < 0.05), indicating that L-arg protects HC rats from renal ischemia. The administration of D-arginine to ND rats induced a significant decrease of the C(in) and a significant increase of FE H2O, FE Na and FE K compared to the L-arginine and not treated groups. Cultures of inner medullary collecting duct cells from ND rats were resistant to 24-h hypoxia. In contrast, IMCD cell cultures from HC rats showed higher LDH release after 24-h hypoxia than normoxic cells (69.2 +/- 3.4 vs. 30.9 +/- 3.6%, P < 0.001); 1 mM L-arg added to the medium attenuated LDH release (44.3 +/- 2.4%, P < 0.01). These data demonstrate that HC predisposes renal tubular cells to hypoxic injury and L-arg protects cells of HC.
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PMID:Protective effect of L-arginine on hypercholesterolemia-enhanced renal ischemic injury. 1021 61

The sequence in which the various therapies discussed above are instituted can be viewed as a continuum that parallels the severity of the underlying cirrhotic state (Figure 6). In the earliest stages of the disease urinary sodium excretion is plentiful and negative salt balance can be achieved by simply lowering dietary sodium intake. As the disease advances neurohumoral effectors become more activated initially resulting in more intense renal salt retention and later in a progressive decline in renal function. Eventually, the filtered load of sodium becomes completely reabsorbed by the tubule and the final urine becomes virtually devoid of salt. If some component of the filtered load reaches the collecting duct or beyond, spironolactone will be effective in increasing urinary sodium excretion. Once sodium reabsorption is complete, proximal to the collecting duct, then thiazides and later loop diuretics will have to be added to spironolactone to increase urinary sodium excretion. Eventually, the filtered load is completely reabsorbed proximal to the thick ascending limb of Henle. At this point the patient is resistant to the effects of diuretics and requires more invasive procedures such as repetitive large volume paracentesis to remain in salt balance. In the terminal stages of the disease the glomerular filtration rate falls to such a degree that oliguria, azotemia, and eventually uremia are present and the patient is clinically diagnosed with hepatorenal syndrome. Vasoconstrictive input focused on the kidney is severe and irreversible. Renal failure is functional in nature; however, restoration of near normal renal function can be obtained following a liver transplant.
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PMID:Pathogenesis of ascites and renal salt retention in cirrhosis. 1036 77

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.
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PMID:Autosomal recessive polycystic kidney disease: radiologic-pathologic correlation. 1083 31

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but devastating inherited disease in humans. Various strains of mice that are homozygous for the cpk gene display renal pathology similar to that seen in human ARPKD. The PKD progresses to renal insufficiency, azotemia, and ultimately a uremic death by approximately 3 wk of age. This study characterizes PKD in mice that are homozygous for the cpk gene on a BALB/c inbred mouse background. The BALB/c-cpk/cpk murine model displays renal as well as extrarenal pathology similar to that found in human ARPKD. The renal pathology includes the well-characterized early proximal tubule and, later, massive collecting duct cysts. The extrarenal defects in this murine model include common bile duct dilation, intrahepatic biliary duct cysts with periductal hyperplasia, and pancreatic dysplasia with cysts. Renal mRNA expression of c-myc, a proto-oncogene, and clusterin (SGP-2), a marker associated with immature collecting ducts, decreases during normal development but is upregulated in murine ARPKD. Expression of epidermal growth factor (EGF) mRNA is significantly diminished, whereas EGF receptor mRNA is upregulated in the BALB/c-cpk/cpk kidney compared with phenotypically normal littermates. To determine whether the altered EGF expression contributes to the development of PKD, neonatal mice were treated with exogenous EGF (1 microg/g body wt injected subcutaneously on postnatal days 3 through 9). EGF treatment reduced the relative kidney weight and common bile duct dilation and downregulated renal expression of clusterin and EGF receptor. However, exogenous EGF did not affect the degree of renal failure, the pancreatic pathology, or the misregulated renal expression of c-myc. In summary, the present study characterizes the renal and extrarenal pathology in the BALB/c-cpk/cpk murine model of ARPKD. Renal mRNA expression of EGF is diminished in this mouse model. EGF treatment did not prevent renal failure but ameliorated pathologic changes in the kidney and the biliary ducts of the BALB/c-cpk/cpk mouse.
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PMID:Development of autosomal recessive polycystic kidney disease in BALB/c-cpk/cpk mice. 1100 14

Collectrin, a novel homolog of angiotensin-converting enzyme-related carboxypeptidase (ACE2), was identified during polymerase chain reaction-based cDNA subtraction and up-regulated in 5/6 ablated kidneys at hypertrophic phase. Collectrin, with 222 amino acids, has an apparent signal peptide and a transmembrane domain; the sequence is conserved in mouse, rat, and human and shares 81.9% identity. Human collectrin has 47.8% identity with non-catalytic extracellular, transmembrane, and cytosolic domains of ACE2; however, unlike ACE and ACE2, collectrin lacks active dipeptidyl carboxypeptidase catalytic domains. The collectrin mRNA transcripts are expressed exclusively in the kidney. In situ hybridization reveals its mRNA expression in renal collecting ducts, and immunohistochemistry shows that it is localized to the luminal surface and cytoplasm of collecting ducts. Immunoprecipitation studies, using [35S]methionine-labeled renal cortical and inner medullar collecting duct cells, i.e. M-1 and mIMCD-3, indicate that the protein size is approximately 32 kDa. During the development of mouse kidney, mRNA signal is detectable at day 13 of gestation, and the protein product is observed in the ureteric bud branches. Its expression is progressively increased during later stages of the gestation extending into the neonatal periods and then is decreased in adult life. Up-regulated expression of collectrin in the hypertrophic kidneys after renal ablation and restricted spatio-temporal expression during development indicates a possible role(s)in the process of progressive renal failure and renal organogenesis.
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PMID:Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. 1127 14

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix (ECM). The membrane-type matrix metalloproteinases (MT-MMPs) are a new family of MMPs that differ from other MMPs in that they have a transmembrane domain that anchors them to the cell surface. MT-MMPs have been shown to function as receptors and activators for other MMPs and to localize extracellular matrix proteolysis at the pericellular region. Here we report on mRNA and protein expression of the fifth human MT-MMP (MT5-MMP), a 64-kDa protein that is capable of converting pro-MMP-2 to its active form, in human kidney as well as its upregulation in diabetes. We also demonstrate upregulation of the active form of MMP-2 in kidney samples from patients with diabetes. Through immunohistochemistry, MT5-MMP expression was localized to the epithelial cells of the proximal and distal tubules, the collecting duct, and the loop of Henle. Furthermore, the tubular epithelial cells that expressed MT5-MMP were associated with tubular atrophy. Because renal tubular atrophy is a significant factor in the pathogenesis of diabetic nephropathy and renal failure and the molecular mechanisms regulating this process remain unknown, it is hypothesized that the elevated expression of MT5-MMP contributes to the activation of pro-MMP-2, which participates in the remodeling of the proximal and distal tubules as well as in the collecting duct. These results provide the first evidence of the expression of a MT-MMP in diabetes and suggest a novel role for MT5-MMP in the pathogenesis of renal tubular atrophy and end-stage renal disease.
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PMID:Upregulated expression of human membrane type-5 matrix metalloproteinase in kidneys from diabetic patients. 1145 23

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.
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PMID:Role of increased circulating and renal adrenomedullin in rats with malignant hypertension. 1170 95

Mutations of either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease, a syndrome characterized by extensive formation of renal cysts and progressive renal failure. Homozygous deletion of Pkd1 or Pkd2, the genes encoding polycystin-1 and polycystin-2, disrupt normal renal tubular differentiation in mice but do not affect the early steps of renal development. Here, we show that expression of the C-terminal 112 amino acids of human polycystin-1 triggers branching morphogenesis and migration of inner medullary collecting duct (IMCD) cells, and support in vitro tubule formation. The integrity of the polycystin-2-binding region is necessary but not sufficient to induce branching of IMCD cells. The C-terminal domain of polycystin-1 stimulated protein kinase C-alpha (PKC-alpha), but not the extracellular signal-regulated kinases ERK1 or ERK2. Accordingly, inhibition of PKC, but not ERK, prevented polycystin-1-mediated IMCD cell morphogenesis. In contrast, HGF-mediated morphogenesis required ERK activation but was not dependent on PKC. Our findings demonstrate that the C-terminal domain of polycystin-1, acting in a ligand-independent fashion, triggers unique signaling pathways for morphogenesis, and likely plays a central role in polycystin-1 function.
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PMID:The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells. 1185 20


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