UNIPROT:P41181 - FACTA Search

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Query: UNIPROT:P41181 (collecting duct)
5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (AII), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAP-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL). EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment. ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.
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PMID:Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments. 874 82

Urea- and NaCl-inducible extracellular signal-regulated kinase (ERK) phosphorylation exhibited dissimilar kinetics. Among cell lines examined, the effect of urea was unique to mIMCD3 inner medullary collecting duct cells and MDCK cells. Urea-inducible ERK activation was approximately 10-fold less sensitive to the MEK inhibitor, PD-98059, than was that of NaCl. This difference did not appear to be accounted for by differential activation of MEK isoforms. Interestingly, the inhibitor of p38 activation, SB-203580, abrogated the effect of both urea and NaCl upon both ERK and MEK activation; however, the former was much less sensitive to the inhibitor. Consistent with this observation, NaCl was much more effective than urea at inducing p38 phosphorylation. The effect of hypertonic stress (e.g., sorbitol 100 mM) could be blocked by appropriate medium dilution such that isotonicity was maintained. In marked contrast, the effect of hyperosmotic urea could not be blocked in this fashion, implying the absence of dependence upon cell volume. Together, these data suggest that cells of the renal inner medulla are potentially uniquely responsive to urea and that urea and hypertonic stressors induce ERK activation through distinct mechanisms.
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PMID:ERK activation by urea in the renal inner medullary mIMCD3 cell line. 1044 71

In the inner medullary collecting duct of the terminal nephron, the type A natriuretic peptide receptor (NPR-A) plays a major role in determining urinary sodium content. This nephron segment, by virtue of its medullary location, is subject to very high levels of extracellular tonicity. We have examined the ability of medium tonicity to regulate the activity and expression of this receptor in cultured rat inner medullary collecting duct cells. We found that NaCl (75 mm) and sucrose (150 mm), but not urea (150 mm), increased natriuretic peptide receptor activity, gene expression, and promoter activity. The osmotic stimulus also activated extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). In the latter instance the beta isoform was selectively activated. Inhibition of p38 MAPK with SB203580 blocked the osmotic induction of receptor activity and expression, as well as receptor gene promoter activity, whereas inhibition of ERK with PD98059 had no effect. Cotransfection of p38 beta MAPK together with the receptor gene promoter resulted in amplification of the osmotic stimulation of the latter, whereas cotransfection of dominant negative MKK6, but not dominant-negative MEK, completely blocked the osmotic induction of receptor promoter activity. Collectively, the data indicate that extracellular osmolality stimulates receptor activity and receptor gene expression through a specific p38 beta-dependent mechanism, raising the possibility that changes in medullary tonicity could play an important role in the regulation of renal sodium handling in the terminal nephron.
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PMID:Osmoregulation of natriuretic peptide receptor signaling in inner medullary collecting duct. A requirement for p38 MAPK. 1174 37

We have previously shown that cultured porcine inner medullary collecting duct cells produce endothelin (ET) which suppressed arginine vasopressin (AVP)-induced cyclic adenosine monophosphate (cAMP) generation in an autocrine/paracrine feedback-like fashion. Moreover, hyperosmolality, e.g. induced by sodium chloride and urea, stimulated ET synthesis. Since others showed that hyperosmolality also activates mitogen-activated protein (MAP) kinases and that p38 MAP kinase facilitates cellular influx of betaine to protect the cell from high extracellular solute (urea) concentrations, we were tempted to investigate a potential interaction of MAP kinases with ET production in cultured MDCK cells in response to extracellular hyperosmolality induced by betaine and urea, respectively. Increased extracellular tonicity (602 +/- 8 vs. control of 323 +/- 3 mosmol/kg H(2)O) induced by betaine stimulated ERK and, more strongly, p38 kinase activity at 0.5-2 h of incubation with a rise in ET-1 synthesis to 1,713 +/- 68 vs. 378 +/- 51 fmol/mg protein/24 h under control conditions (p < 0.01). The p38 MAP kinase inhibitor SB203580 suppressed the rise in betaine-induced ET-1 synthesis by 91% to 494 +/- 38 fmol/mg protein/24 h, whereas the MEK/ERK inhibitor U0126 suppressed it moderately by 34%. Hypertonicity induced by urea moderately stimulated ERK but not p38 MAP kinase activity at 0.5-2 h and at 24-48 h and resulted in a modest rise in ET-1 synthesis to 681 +/- 61 fmol/mg protein/24 h (p < 0.05) which was significantly suppressed by U0126 to 484 +/- 16 fmol/mg protein/24 h. These results suggest that a functional interaction between the MAP kinases ERK and p38 MAP kinase and ET-1 synthesis is involved in betaine's protection of MDCK cells in vitro which may represent an in vivo mechanism of protection from hyperosmotic stress induced by high extracellular solute concentrations.
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PMID:Hyperosmolality induced by betaine or urea stimulates endothelin synthesis by differential activation of ERK and p38 MAP kinase in MDCK cells. 1207 86

Bcl-2 protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Bcl-2 -/- mice develop renal hypoplastic/cystic dysplasia with renal cyst formation coinciding with renal maturation in normal mice. To gain a better understanding of the role cell-adhesive mechanisms play during renal maturation, we generated proximal tubule and collecting duct cell lines from postnatal day 10 (P10) and P20 bcl-2 +/+ and bcl-2 -/- mice. Very little is known about the role cell-adhesive and migratory mechanisms play during renal maturation. We observed that modulation of cell-adhesive properties, which normally occur in a nephron segment-specific manner during renal maturation, and cell migration were altered in cells from bcl-2 -/- mice. Enhanced migration of bcl-2 -/- proximal tubule cells in a scratch wound assay was completely inhibited by incubation with PP1 (Src inhibitor) and moderately affected by incubation with SB-203580 (p38 inhibitor). These cells expressed increased levels of fibronectin and had numerous central focal adhesions. P20 bcl-2 -/- proximal tubule cells adhered to fibronectin but adhered poorly to collagen, vitronectin, or laminin. Collecting duct cells, similar to proximal tubule cells from bcl-2 -/- mice, demonstrated enhanced migration in a scratch wound assay that was inhibited by incubation with PP1. Migration of these cells was moderately affected by incubation with PD-98059 (MEK inhibitor) or LY-294002 (PI3 kinase inhibitor), whereas incubation with SB-203580 had no effect. P10 bcl-2 -/- collecting duct cells also expressed increased levels of fibronectin but decreased levels of thrombospondin-1 and demonstrated precocious binding to fibronectin and vitronectin compared with bcl-2 +/+ cells. The ability of P20 bcl-2 +/+ collecting duct cells to adhere to fibronectin and vitronectin corresponded with a decline in thrombospondin-1 expression. Therefore, alterations in cell-adhesive and migratory characteristics may be an early indicator of aberrant renal epithelial cell differentiation.
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PMID:Alterations in cell-adhesive and migratory properties of proximal tubule and collecting duct cells from bcl-2 -/- mice. 1529 44

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.
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PMID:Therapies to slow polycystic kidney disease. 1536 92

The mechanism by which cells sense extracellular tonicity and trigger the accumulation of protective organic osmolytes is poorly understood. It has been proposed that changes in cell volume following alteration of extracellular toncity are important initiators of signaling events that lead to osmolyte accumulation. Because the extracellular matrix receptors integrins are linked to the cytoskeleton and can transduce signals that alter cell behavior, we investigated the role of these receptors in the modulation of osmolyte accumulation in the kidney medulla under different osmotic conditions. We show that integrin alpha1-null mice have impaired ability to accumulate organic osmolytes in the inner medulla due to altered signaling and decreased induction of osmolyte transporters or aldose reductase gene transcription. Utilizing inner medullary collecting duct cells, we demonstrate that the lack of integrin alpha1beta1 results in an impaired ability to induce the tonicity enhancer-binding protein TonEBP under hypertonic conditions. Furthermore, under the same conditions, integrin alpha1-null cells show prolonged ERK1/2 phosphorylation and decreased inositol uptake compared with control cells. The reduction of inositol uptake is significantly reversed by treatment with the MEK inhibitor PD-98059. Finally, integrin alpha1-null mice develop morphological changes of early tubular necrosis and increased apoptosis of renal medullary cells following dehydration. Together, these results show that integrin alpha1beta1 is an important mediator of the compatible osmolyte response in the medulla of the mammalian kidney.
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PMID:Role of integrin alpha1beta1 in the regulation of renal medullary osmolyte concentration. 1610 35

Polycystic kidney disease (PKD) is a lethal disorder characterized by progressive expansion of renal cysts. Genetic mutations associated with PKD are thought to disrupt intracellular Ca2+ regulation, leading to abnormal proliferation of tubule epithelial cells. cAMP stimulates the B-Raf/MEK/extracellular signal-regulated kinase (B-Raf/MEK/ERK) pathway and accelerates the proliferation of cells that are cultured from PKD cysts. By contrast, cAMP inhibits the proliferation of cells from normal human kidneys (NHK) and M-1 mouse collecting duct cells. Previously, it was found that a sustained reduction of intracellular Ca2+ levels in NHK and M-1 cells that were treated with Ca2+ entry blockers allowed cAMP activation of the B-Raf/MEK/ERK pathway, switching the cells to a cAMP-growth stimulated phenotype. In this study, primary cultures of cyst epithelial cells from autosomal dominant (ADPKD) and recessive (ARPKD) PKD kidneys were used to determine whether controlled addition of Ca2+ could reverse the aberrant mitogenic response to cAMP. Steady-state intracellular Ca2+ levels were found to be 20 nM lower in cyst-derived ADPKD cells (57 +/- 2 nM) compared with NHK cells (77 +/- 2 nM). Treatment of ADPKD cells or ARPKD cells with either Bay K8644, a Ca2+ channel activator, or A23187, a Ca2+ ionophore, caused sustained increases in intracellular Ca2+ levels and completely reversed the mitogenic response to cAMP. Elevation of intracellular Ca2+ levels in ADPKD cells increased Akt activity and blocked cAMP-dependent B-Raf and ERK activation. Thus, increases in [Ca2+]i are able to restore the normal anti-mitogenic response to cAMP in cells that are derived from two genetically distinct forms of PKD.
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PMID:Calcium restores a normal proliferation phenotype in human polycystic kidney disease epithelial cells. 1631 89

Aldosterone is the principal hormonal regulator of sodium homeostasis in vertebrates. It exerts its actions through the mineralocorticoid receptor (MR) that regulates the transcription of specific target genes. In recent years, a number of MR target genes have been identified that are involved in the regulation of the epithelial sodium channel (ENaC), a key modulator of renal sodium absorption. Here we report the identification of cnksr3 as a direct MR target gene that is up-regulated in response to physiological concentrations of aldosterone. The cnksr3 promoter exhibits two functional aldosterone-responsive regions, which were bound by the MR as assessed by chromatin immunoprecipitation (ChIP). In vivo, CNKSR3 was highly expressed in the renal cortical collecting duct (CCD), the prime target segment of aldosterone-regulated sodium retention in the kidney. CCD cell lines stably overexpressing or silencing CNKSR3 were electrophysiologically analyzed and show that CNKSR3 expression correlated with and is required for ENaC-mediated transepithelial sodium transport. In parallel, CNKSR3 expression led to decreased MEK phosphorylation. We conclude that CNKSR3, a homologue of scaffold proteins involved in MAPK pathway regulation, is a direct target of MR and is required for the maintenance of transepithelial sodium transport in the kidney.
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PMID:Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. 1956 70

Alteration of the tight junction complex in renal epithelial cells can affect renal barrier function and perturb normal kidney homeostasis. The immunosuppressant drugs cyclosporine A (CsA) and sirolimus (SRL) used in combination demonstrated beneficial effects in organ transplantation but this combination can also result in increased adverse effects. We previously showed that CsA treatment alone caused an alteration of the tight junction complex, resulting in changes in transepithelial permeability in Madin-Darby canine kidney distal tubular/collecting duct cells. The potential effect of SRL on transepithelial permeability in kidney cells is unknown. In this study, subcytotoxic doses of SRL or CsA were found to decrease the paracellular permeability of the porcine proximal tubular epithelial cells, LLC-PK1 cell monolayers, which was detected as an increase in transepithelial electrical resistance (TER). The cotreatment with SRL and CsA was found to increase TER in a synergistic manner. CsA treatment increased total cellular expression and membrane localization of the tight junction protein claudin-1 and this further increased with the combination of SRL/CsA. SRL and CsA treatment alone or in combination stimulated the phosphorylation of ERK1/2. The MEK-ERK1/2 pathway inhibitor, U0126, reduced the SRL, CsA, and CsA/SRL-induced increase in TER. U0126 also reduced the CsA and CsA/SRL-induced increase in the membrane localization of claudin-1. Alterations in claudin-2 and claudin-4 were also detected. However, the results suggest that the modulation in expression and localization of claudin-1 appears to be pivotal in the SRL- and CsA-induced modulation of the epithelial barrier function and that modulation is regulated by ERK1/2 signaling pathway.
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PMID:Sirolimus and cyclosporine A alter barrier function in renal proximal tubular cells through stimulation of ERK1/2 signaling and claudin-1 expression. 1995 89

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