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)

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

Due to urea's role in producing concentrated urine, its transport is critically important to the conservation of body water. Within the renal inner medulla, urea is transported by both facilitated and active urea transport mechanisms. The vasopressin-regulated, facilitated urea transporter (UT-A1) in the terminal inner medullary collecting duct (IMCD) permits high rates of transepithelial urea transport and results in delivery of large quantities of urea into the deepest portions of the inner medulla where it is needed to maintain a high interstitial osmolality for maximal urine concentration. Four cDNA isoforms of the UT-A urea transporter family have been cloned. In addition, there are three secondary active, sodium-dependent, urea transport mechanisms in IMCD subsegments: (1) active urea secretion in the apical membrane of the terminal IMCD from untreated rats; (2) active urea absorption in the apical membrane of the initial IMCD from low-protein fed or hypercalcemic rats; and (3) active urea absorption in the basolateral membrane of the initial IMCD from furosemide-treated rats. This review will focus on integrative studies of the rapid and long-term regulation of urea transporters in rats with reduced urine concentrating ability. These studies led to the surprising result that the basal-facilitated urea permeability in the terminal IMCD and UT-A1 protein abundance are increased during in vivo conditions associated with an impaired urine concentrating ability. In contrast, there are two response patterns of active urea transporters: (1) hypercalcemia, a low-protein diet, and furosemide result in induction of active urea absorption in the initial IMCD, albeit by different mechanisms, and inhibition of active urea secretion in the terminal IMCD; while (2) water diuresis results in up-regulation of active urea secretion in the terminal IMCD without any active urea absorption in the initial IMCD. The first pattern contributes to the urine concentrating defect by increasing urea delivery to the base of the inner medulla, thus decreasing urea delivery distally to the inner medullary tip. The second response pattern will directly decrease urea content in the deep inner medulla. UT-A urea transporters are also expressed outside the kidney. Recent studies show that the liver has phloretin-inhibitable urea transport and that it occurs via a 49 kDa UT-A protein. When rats are made uremic, the abundance of this 49 kDa UT-A protein increases in the liver in vivo. This up-regulation of the 49 kDa UT-A protein may allow hepatocytes to increase ureagenesis to reduce the accumulation of ammonium and/or bicarbonate in uremia.
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PMID:Regulation of urea transporter proteins in kidney and liver. 1074 66

Urea plays a critical role in the urine-concentrating mechanism in the inner medulla. Physiologic data provided evidence that urea transport in red blood cells and kidney inner medulla was mediated by specific urea transporter proteins. Molecular approaches during the past decade resulted in the cloning of two gene families for facilitated urea transporters, UT-A and UT-B, encoding several urea transporter cDNA isoforms in humans, rodents, and several nonmammalian species. Polyclonal antibodies have been generated to the cloned urea transporter proteins, and the use of these antibodies in integrative animal studies has resulted in several novel findings, including: (1) the surprising finding that UT-A1 protein abundance and urea transport are increased in the inner medulla during conditions in which urine concentrating ability is reduced; (2) vasopressin increases UT-A1 phosphorylation in rat inner medullary collecting duct; (3) UT-A protein abundance is upregulated in uremia in both liver and heart; and (4) UT-B is expressed in many nonrenal tissues and endothelial cells. This review will summarize the knowledge gained from using molecular approaches to perform integrative studies into urea transporter protein regulation, both in normal animals and in animal models of human diseases, including studies of uremic rats in which urea transporter protein is upregulated in liver and heart.
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PMID:Molecular approaches to urea transporters. 1239 52

Urea plays a key role in the urine-concentrating mechanism. Physiologic and molecular data demonstrate that urea transport in kidney and red blood cells occurs by specific urea transporter proteins. Two gene families for facilitated urea transporters, UT-A and UT-B, and several urea transporter cDNA isoforms have been cloned from human, rat, mouse, and several non-mammalian species. Polyclonal antibodies have been generated to many of the urea transporter proteins, and several novel findings have resulted from their use in integrative animal studies. For example, (a) vasopressin increases the phosphorylation of UT-A1 in rat inner medullary collecting duct; (b) UT-A1 protein abundance is increased in the rat inner medulla during conditions in which urine-concentrating ability is reduced; and (c) urea transporters are expressed in non-renal tissues, and UT-A protein abundance is up-regulated in uremia in both liver and heart. In addition to the facilitated urea transporters, functional evidence exists for active urea transport in the kidney collecting duct. This review summarizes the physiologic evidence for the existence of facilitated and active urea transporters, the molecular biology of the facilitated urea transporter gene families and cDNAs, and integrative studies into urea transporter protein regulation, both in the kidney and in other organs.
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PMID:Mammalian urea transporters. 1252 63

Physiologic data provided evidence for specific urea transporter proteins in red blood cells and kidney inner medulla. During the past decade, molecular approaches resulted in the cloning of several urea transporter cDNA isoforms derived from two gene families: UT-A and UT-B. Polyclonal antibodies were generated to the cloned urea transporter proteins, and their use in integrative animal studies resulted in several novel findings, including: (1) UT-B is the Kidd blood group antigen; (2) UT-B is also expressed in many non-renal tissues and endothelial cells; (3) vasopressin increases UT-A1 phosphorylation in rat inner medullary collecting duct; (4) the surprising finding that UT-A1 protein abundance and urea transport are increased in the inner medulla during conditions in which urine concentrating ability is reduced; and (5) UT-A protein abundance is increased in uremia in both liver and heart. This review will summarize the knowledge gained from studying molecular mechanisms of urea transport and from integrative studies into urea transporter protein regulation.
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PMID:Molecular mechanisms of urea transport. 1257 50

Erythrocytes are useful in evaluating K+ transport pathways involved in internal K+ balance. Several forms of H+,K+-ATPase have been described in nephron segments active in K+ transport. Furthermore, the activity of a ouabain-insensitive isoform of H+,K+-ATPase expressed in collecting duct cells may be modulated by acid-base status. Various assays were performed to determine if a ouabain-insensitive K+-ATPase is present in rat erythrocytes and, if so, whether it plays a role in internal K+ balance. Kinetic studies demonstrated that maximal stimulation of enzyme activity was achieved with 2.5 mM K+ at pH 7.4. Subsequent experiments were performed on erythrocyte membranes collected from animals submitted to varying degrees of K+ homeostasis: control rats, K+-depleted rats, K+-loaded rats, and rats rendered hyperkalemic due to acute renal failure. As observed in the collecting duct cell studies, there was a significant decrease in the activity of ouabain-insensitive K+-ATPase in the erythrocytes of both K+-loaded and metabolically alkalotic K+-depleted rats. However, this enzyme activity in erythrocyte membranes of rats with metabolic acidosis-related hyperkalemia was similar to that of control animals. This finding may be interpreted as resulting from two potentially modulating factors: the stimulating effect that metabolic acidosis has on K+-ATPase and the counteracting effect that hyperkalemia and uremia have on metabolic acidosis. In summary, we present evidence of a ouabain-insensitive K+-ATPase in erythrocytes, whose activity is modulated by acid-base status and K+ levels.
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PMID:Erythrocytes may contain a ouabain-insensitive K+-ATPase which plays a role in internal K+ balance. 1466 63

Deficiency of tumor suppressor FLCN leads to the activation of the mTOR signaling pathway in human BHD-associated renal cell carcinomas (RCC). We have previously developed a renal distal tubule-collecting duct-Henle's loop-specific Flcn knockout (KO) mouse model (Flcnflox/flox/Ksp-Cre). This mouse model can only survive for three weeks after birth due to the development of polycystic kidney and uremia. Whether these cystic solid hyperplasia changes seen in those KO mice are tumorigenic or malignant is unknown. In this study, we demonstrated that genetic disruption of Flcn in mouse kidney distal tubule cells could lead to tumorigenic transformation of these cells to develop allograft tumors with an aggressive histologic phenotype. Consistent with previous reports, we showed that the mTOR pathway plays an important role in the growth of these Flcn-deficient allograft and human UOK 257-1 xenograft tumors. We further demonstrated that the mTOR inhibitor, sirolimus, suppresses the tumor's growth, suggesting that mTOR inhibitors might be effective in control of FLCN-deficient RCC, especially in BHD renal tumorigenesis.
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PMID:Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression. 2641 49