scholarly journals A Polycystin-1 Multiprotein Complex Is Disrupted in Polycystic Kidney Disease Cells

2004 ◽  
Vol 15 (3) ◽  
pp. 1334-1346 ◽  
Author(s):  
Tamara Roitbak ◽  
Christopher J. Ward ◽  
Peter C. Harris ◽  
Robert Bacallao ◽  
Scott A. Ness ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cell Function ◽  
Protein Complexes ◽  
Adherens Junction ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell ◽  
Junction Protein ◽  
E Cadherin

Autosomal dominant polycystic kidney disease (ADPKD) is typified by the accumulation of fluid-filled cysts and abnormalities in renal epithelial cell function. The disease is principally caused by mutations in the gene encoding polycystin-1, a large basolateral plasma membrane protein expressed in kidney epithelial cells. Our studies reveal that, in normal kidney cells, polycystin-1 forms a complex with the adherens junction protein E-cadherin and its associated catenins, suggesting a role in cell adhesion or polarity. In primary cells from ADPKD patients, the polycystin-1/polycystin-2/E-cadherin/β-catenin complex was disrupted and both polycystin-1 and E-cadherin were depleted from the plasma membrane as a result of the increased phosphorylation of polycystin-1. The loss of E-cadherin was compensated by the transcriptional upregulation of the normally mesenchymal N-cadherin. Increased cell surface N-cadherin in the disease cells in turn stabilized the continued plasma membrane localization of β-catenin in the absence of E-cadherin. The results suggest that enhanced phosphorylation of polycystin-1 in ADPKD cells precipitates changes in its localization and its ability to form protein complexes that are critical for the stabilization of adherens junctions and the maintenance of a fully differentiated polarized renal epithelium.

scholarly journals Compromised Cytoarchitecture and Polarized Trafficking in Autosomal Dominant Polycystic Kidney Disease Cells

2000 ◽  
Vol 149 (1) ◽  
pp. 111-124 ◽  
Author(s):  
Audra J. Charron ◽  
Sakie Nakamura ◽  
Robert Bacallao ◽  
Angela Wandinger-Ness
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Spatial Organization ◽  
Autosomal Dominant ◽  
Basolateral Membrane ◽  
Polycystic Kidney ◽  
Junction Protein ◽  
Autosomal Dominant Polycystic Kidney ◽  
Basolateral Trafficking ◽  
E Cadherin

Cystogenesis associated with autosomal dominant polycystic kidney disease (ADPKD) is characterized by perturbations in the polarized phenotype and function of cyst-lining epithelial cells. The polycystins, the protein products of the genes mutated in the majority of ADPKD cases, have been described recently, but the pathological mechanism by which causal mutations result in the mislocalization of cell membrane proteins has remained unclear. This report documents the dissociation from the ADPKD cell basolateral membrane of three molecules essential for spatial organization and exocytosis. The adherens junction protein E-cadherin, the subcellular disposition of which governs intercellular and intracellular architecture, was discovered sequestered in an internal ADPKD cell compartment. At the same time, sec6 and sec8, components of a complex critical for basolateral cargo delivery normally arrayed at the apico-lateral apex, were depleted from the ADPKD cell plasma membrane. An analysis of membrane transport revealed that basolateral trafficking of proteins and lipids was impaired as a result of delayed cargo exit from the ADPKD cell Golgi apparatus. Apical transport proceeded normally. Taken together with recent documentation of an association between polycystin-1 and E-cadherin (Huan and van Adelsberg 1999), the data suggest that causal mutations disrupt E-cadherin–dependent cytoarchitecture, adversely affecting protein assemblies crucial for basolateral trafficking.

Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

2011 ◽  
Vol 300 (2) ◽  
pp. F511-F520 ◽  
Author(s):  
Hiroko Togawa ◽  
Koichi Nakanishi ◽  
Hironobu Mukaiyama ◽  
Taketsugu Hama ◽  
Yuko Shima ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Contact ◽  
Polycystic Kidney ◽  
Mesenchymal Transition ◽  
Cyst Lining ◽  
E Cadherin

In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.

Attenuated expression of epithelial cell adhesion molecules in murine polycystic kidney disease

1992 ◽  
Vol 262 (4) ◽  
pp. F679-F686 ◽  
Author(s):  
M. V. Rocco ◽  
E. G. Neilson ◽  
J. R. Hoyer ◽  
F. N. Ziyadeh
Keyword(s):  
Cell Adhesion ◽  
Growth Factors ◽  
Kidney Disease ◽  
Adhesion Molecules ◽  
Polycystic Kidney Disease ◽  
Cell Adhesion Molecules ◽  
Structural Proteins ◽  
Polycystic Kidney ◽  
Cystic Kidneys ◽  
E Cadherin

Polycystic kidney disease is an inherited disorder of parenchymal structure that leads to renal failure. Cysts begin as focal dilations in proximal tubules and collecting ducts, giving rise to cyst walls lined by a phenotypically disturbed epithelium that expresses dysfunctional transport and matrix proteins. We used an mRNA search protocol to probe efficiently for tissue-specific disturbances that might underlie the formation of cysts. This search assessed the relative abundance of transcripts encoding a variety of growth factors (transforming growth factor-beta 1, interleukin-6, tumor necrosis factor, and endothelin-1), structural proteins (collagen IV, nidogen, fibronectin, and laminins A and B1), and cell adhesion molecules (CAMs; E-cadherin, N-CAM, laminin receptor, and fibronectin receptor) in the cystic kidneys of cpk/cpk mice and uncovered a previously unrecognized early reduction in mRNA encoding N-CAM (54%) and E-cadherin (56%) (n = 5; P less than 0.001). Levels of transcripts for growth factors, structural proteins, and for fibronectin and laminin receptors in normal and cystic kidneys were generally similar. The reduction in transcripts for N-CAM and E-cadherin in kidneys from cystic mice was not observed in autologous liver. The immunofluorescent staining of cystic kidneys confirmed that the decrease in N-CAM and E-cadherin was generally confined to regions abundant in developing cystic epithelium. The presence of both N-CAM and E-cadherin appears to guide the sequential differentiation and polarization of normal renal epithelium, and their attenuated expression in the kidney of cpk/cpk mice may be a material factor contributing to the pathogenesis of cyst formation.

Polycystic kidney disease and receptor for egg jelly is a plasma membrane protein of mouse sperm head

2006 ◽  
Vol 73 (3) ◽  
pp. 350-360 ◽  
Author(s):  
Yulia Butscheid ◽  
Vladimir Chubanov ◽  
Klaus Steger ◽  
Dorke Meyer ◽  
Alexander Dietrich ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Kidney Disease ◽  
Membrane Protein ◽  
Polycystic Kidney Disease ◽  
Sperm Head ◽  
Plasma Membrane Protein ◽  
Polycystic Kidney ◽  
Mouse Sperm ◽  
Egg Jelly

scholarly journals The cell biology of polycystic kidney disease

2010 ◽  
Vol 191 (4) ◽  
pp. 701-710 ◽  
Author(s):  
Hannah C. Chapin ◽  
Michael J. Caplan
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cell Biology ◽  
Fluid Transport ◽  
Genetic Disorder ◽  
Growth Control ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell ◽  
Autosomal Dominant Polycystic Kidney

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets.

P0041CHARACTERISTICS OF URINE-DERIVED RENAL EPITHELIAL CELLS (UREC) FROM CHILDREN WITH POLYCYSTIC KIDNEY DISEASE (PKD)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Wolfgang H Ziegler ◽  
Sarah Lüdiger ◽  
Charlotte Mett ◽  
Fatema Hasan ◽  
Birga Soetje ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cell ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Cell Function ◽  
Ex Vivo ◽  
3D Culture ◽  
Primary Cells ◽  
Polycystic Kidney ◽  
Genetic Origin

Abstract Background and Aims In hereditary PKD, epithelial cell defects are mostly caused by mutation of proteins of the cilia-centrosome complex. Use of primary cells from patients allows to study specific cell characteristics and altered activation of signal pathways in epithelial cell function-related culture models. In this ex vivo approach, comparison of cell properties is based on defined genetic origin and can be related to kidney function at the time of UREC collection, revealing consequences of genetic disposition and kidney-stress related changes on cell function. Method The study considers patients with genetically confirmed causes of PKD, autosomal recessive polycystic kidney disease (ARPKD), nephronophtisis (NPH), Bardet-Biedl syndrome (BBS), and age-matched controls with normal kidney function. UREC are grown from cellular urine sediment using selective growth conditions. Primary cells are cultured up-to 21 days (passages 2 & 3) and tested with respect to their proliferation, tubular origin and epithelial properties in 2D/3D culture conditions. To allow pathway analysis and improve control conditions, immortalized UREC lines are also included. Results UREC preparations of cohorts from ARPKD, NPH, and BBS patients, and controls were studied quantitatively to determine specific epithelial cell properties. Considering basic characteristics of each primary culture including cell morphology, expression of epithelial markers, and formation of cell-cell adhesions, the potential of UREC cells to polarize and generate liquid-filled epithelial spheroids was measured. The capacity of lumen formation in 3D culture strongly varies among individual cell preparations and appears to reflect the genetic origin of UREC cells, whereas no correlation to (remaining) kidney function (eGFR) is observed. Conclusion Determining specific, quantitative UREC cell properties related to genetics and kidney function, we expect to gain a better mechanistic understanding of cellular and renal epithelial defects in PKD patients. Ex vivo analysis based on UREC cells may provide options for testing of personalized pharmaceutical intervention.

scholarly journals Hedgehog signaling regulates E-cadherin expression for the maintenance of the actin cytoskeleton and tight junctions

2010 ◽  
Vol 299 (6) ◽  
pp. G1252-G1265 ◽  
Author(s):  
Chang Xiao ◽  
Sally A. Ogle ◽  
Michael A. Schumacher ◽  
Neal Schilling ◽  
Robert A. Tokhunts ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cell ◽  
Tight Junctions ◽  
Hedgehog Signaling ◽  
Protein Complexes ◽  
Cell Lineage ◽  
Adherens Junction ◽  
Epithelial Cell Differentiation ◽  
Junction Protein ◽  
E Cadherin

In the stomach, strictly regulated cell adherens junctions are crucial in determining epithelial cell differentiation. Sonic Hedgehog (Shh) regulates epithelial cell differentiation in the adult stomach. We sought to identify whether Shh plays a role in regulating adherens junction protein E-cadherin as a mechanism for epithelial cell differentiation. Mouse nontumorigenic gastric epithelial (IMGE-5) cells treated with Hedgehog signaling inhibitor cyclopamine and anti-Shh 5E1 antibody or transduced with short hairpin RNA against Skinny Hedgehog (IMGE-5Ski) were cultured. A mouse model expressing a parietal cell-specific deletion of Shh (HKCre/ShhKO) was used to identify further changes in adherens and tight junctions. Inhibition of Hedgehog signaling in IMGE-5 cells caused loss of E-cadherin expression accompanied by disruption of F-actin cortical expression and relocalization of zonula occludens-1 (ZO-1). Loss of E-cadherin was also associated with increased proliferation in IMGE-5Ski cells and increased expression of the mucous neck cell lineage marker MUC6. Compared with membrane-expressed E-cadherin and ZO-1 protein in controls, dissociation of E-cadherin/β-catenin and ZO-1/occludin protein complexes was observed in HKCre/ShhKO mice. In conclusion, we demonstrate that Hedgehog signaling regulates E-cadherin expression that is required for the maintenance of F-actin cortical expression and stability of tight junction protein ZO-1.

scholarly journals Non-Coding RNAs in Hereditary Kidney Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 3014
Author(s):  
Julie Xia Zhou ◽  
Xiaogang Li
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Single Gene ◽  
Noncoding Rnas ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell ◽  
Von Hippel Lindau ◽  
Non Coding Rnas

Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 gene. Due to the complexity of pathophysiology of cyst formation and progression, limited therapeutic options are available. The roles of noncoding RNAs in development and disease have gained widespread attention in recent years. In particular, microRNAs in promoting PKD progression have been highlighted. The dysregulated microRNAs modulate cyst growth through suppressing the expression of PKD genes and regulating cystic renal epithelial cell proliferation, mitochondrial metabolism, apoptosis and autophagy. The antagonists of microRNAs have emerged as potential therapeutic drugs for the treatment of ADPKD. In addition, studies have also focused on microRNAs as potential biomarkers for ADPKD and other common hereditary kidney diseases, including HNF1β-associated kidney disease, Alport syndrome, congenital abnormalities of the kidney and urinary tract (CAKUT), von Hippel–Lindau (VHL) disease, and Fabry disease. This review assembles the current understanding of the non-coding RNAs, including microRNAs and long noncoding RNAs, in polycystic kidney disease and these common monogenic kidney diseases.

Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney

2015 ◽  
Vol 308 (9) ◽  
pp. F1004-F1011 ◽  
Author(s):  
EunSun Chang ◽  
Eun Young Park ◽  
Yu mi Woo ◽  
Duk-Hee Kang ◽  
Young-Hwan Hwang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Renal Function ◽  
Multidrug Resistance ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Drug Targets ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance-associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD.

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