scholarly journals PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells

2004 ◽  
Vol 101 (8) ◽  
pp. 2311-2316 ◽  
Author(s):  
M.-Z. Zhang ◽  
W. Mai ◽  
C. Li ◽  
S.-y. Cho ◽  
C. Hao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Primary Cilia ◽  
Basal Bodies ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells

Mechanoregulation of intracellular Ca2+ in human autosomal recessive polycystic kidney disease cyst-lining renal epithelial cells

2008 ◽  
Vol 294 (4) ◽  
pp. F890-F899 ◽  
Author(s):  
Rajeev Rohatgi ◽  
Lorenzo Battini ◽  
Paul Kim ◽  
Sharon Israeli ◽  
Patricia D. Wilson ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Cell Lines ◽  
Autosomal Recessive ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Collecting Tubule ◽  
Intracellular Ca ◽  
Cyst Lining

Mutations of cilia-expressed proteins are associated with an attenuated shear-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in renal epithelial cell lines derived from murine models of autosomal recessive polycystic kidney disease (ARPKD). We hypothesized that human ARPKD cyst-lining renal epithelial cells also exhibited dysregulated mechanosensation. To test this, conditionally immortalized cell lines derived from human fetal ARPKD cyst-lining (pool and clone 5E) cell lines with low levels of fibrocystin/polyductin expression and age-matched normal collecting tubule [human fetal collecting tubule (HFCT) pool and clone 2C] cell lines were grown in culture, loaded with a Ca2+ indicator dye, and subjected to laminar shear. Clonal cell lines were derived from single cells present in pools of cells from cyst-lining and collecting tubules, microdissected from human kidney. Resting and peak [Ca2+]i were similar between ARPKD 5E and pool, and HFCT 2C and pool; however, the flow-induced peak [Ca2+]i was greater in ARPKD 5E (700 ± 87 nM, n = 21) than in HFCT 2C (315 ± 58 nM, n = 12; P < 0.01) cells. ARPKD 5E cells treated with Gd3+, an inhibitor of nonselective cation channels, inhibited but did not abolish the shear-induced [Ca2+]i transient. Cilia were ∼20% shorter in ARPKD than HFCT cells, but no difference in ciliary localization or total cellular expression of polycystin-2, a mechanosenory Gd3+-sensitive cation channel, was detected between ARPKD and HFCT cells. The intracellular Ca2+ stores were similar between cells. In summary, human ARPKD cells exhibit an exaggerated Gd3+-sensitive mechano-induced Ca2+ response compared with controls; whether this represents dysregulated polycystin-2 activity in ARPKD cells remains to be explored.

scholarly journals Autosomal Recessive Polycystic Kidney Disease Epithelial Cell Model Reveals Multiple Basolateral Epidermal Growth Factor Receptor Sorting Pathways

2010 ◽  
Vol 21 (15) ◽  
pp. 2732-2745 ◽  
Author(s):  
Sean Ryan ◽  
Susamma Verghese ◽  
Nicholas L. Cianciola ◽  
Calvin U. Cotton ◽  
Cathleen R. Carlin
Keyword(s):  
Kidney Disease ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Egf Receptor ◽  
Cell Model ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells

Sorting and maintenance of the EGF receptor on the basolateral surface of renal epithelial cells is perturbed in polycystic kidney disease and apical expression of receptors contributes to severity of disease. The goal of these studies was to understand the molecular basis for EGF receptor missorting using a well-established mouse model for the autosomal recessive form of the disease. We have discovered that multiple basolateral pathways mediate EGF receptor sorting in renal epithelial cells. The polycystic kidney disease allele in this model, Bicc1, interferes with one specific EGF receptor pathway without affecting overall cell polarity. Furthermore one of the pathways is regulated by a latent basolateral sorting signal that restores EGF receptor polarity in cystic renal epithelial cells via passage through a Rab11-positive subapical compartment. These studies give new insights to possible therapies to reconstitute EGF receptor polarity and function in order to curb disease progression. They also indicate for the first time that the Bicc1 gene that is defective in the mouse model used in these studies regulates cargo-specific protein sorting mediated by the epithelial cell specific clathrin adaptor AP-1B.

scholarly journals Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Ding ◽  
Linda Xiaoyan Li ◽  
Peter C. Harris ◽  
Junwei Yang ◽  
Xiaogang Li
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Extracellular Vesicles ◽  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

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.

Autosomal recessive polycystic kidney disease

2015 ◽  
Author(s):  
Carsten Bergmann ◽  
Klaus Zerres
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Primary Cilia ◽  
Transmembrane Protein ◽  
Phenotypic Variability ◽  
Amino Acid Type ◽  
Polycystic Kidney ◽  
Exact Function ◽  
The Individual

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality with variable disease expression. Many patients manifest peri- or neonatally with a mortality rate of 30–50%, whereas others survive to adulthood with only minor clinical features. ARPKD is typically caused by mutations in the PKHD1 gene that encodes a 4074-amino acid type 1 single-pass transmembrane protein called fibrocystin or polyductin. Fibrocystin/polyductin is among other cystoproteins expressed in primary cilia, basal bodies, and centrosomes, but its exact function has still not been fully unravelled. Mutations were found to be scattered throughout the gene with many of them being private to single families. Correlations have been drawn for the type of mutation rather than for the site of the individual mutation. Virtually all patients carrying two truncating mutations display a severe phenotype with peri- or neonatal demise while surviving patients bear at least one hypomorphic missense mutation. However, about 20–30% of all sibships exhibit major intrafamilial phenotypic variability and it becomes increasingly obvious that ARPKD is clinically and genetically much more heterogeneous and complex than previously thought.

scholarly journals 20-HETE Mediates Proliferation of Renal Epithelial Cells in Polycystic Kidney Disease

2008 ◽  
Vol 19 (10) ◽  
pp. 1929-1939 ◽  
Author(s):  
Frank Park ◽  
William E. Sweeney ◽  
Guangfu Jia ◽  
Richard J. Roman ◽  
Ellis D. Avner
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells

scholarly journals Abnormalities in focal adhesion complex formation, regulation, and function in human autosomal recessive polycystic kidney disease epithelial cells

2010 ◽  
Vol 298 (4) ◽  
pp. C831-C846 ◽  
Author(s):  
Sharon Israeli ◽  
Kurt Amsler ◽  
Nadezhda Zheleznova ◽  
Patricia D. Wilson
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Complex Formation ◽  
Polycystic Kidney Disease ◽  
Focal Adhesion ◽  
Autosomal Recessive ◽  
Polycystic Kidney ◽  
Focal Adhesion Complex ◽  
Collecting Tubules ◽  
Adhesion Complex

Integrin-associated focal adhesion complex formation and turnover plays an essential role in directing interactions between epithelial cells and the extracellular matrix during organogenesis, leading to appropriate cell spreading, cell-matrix adhesion, and migration. Autosomal recessive polycystic kidney disease (ARPKD) is associated with loss of function of PKHD1-encoded protein fibrocystin-1 and is characterized by cystic dilation of renal collecting tubules (CT) in utero and loss of renal function in patients if they survive the perinatal period. Normal polycystin-1 (PC-1)/focal adhesion complex function is required for control of CT diameter during renal development, and abnormalities in these complexes have been demonstrated in human PC-1 mutant cystic cells. To determine whether loss of fibrocystin-1 was associated with focal adhesion abnormalities, ARPKD cells or normal age-matched human fetal (HF)CT cells in which fibrocystin-1 had been decreased by 85% by small interfering RNA inhibition were compared with normal HFCT. Accelerated attachment and spreading on collagen matrix and decreased motility of fibrocystin-1-deficient cells were associated with longer paxillin-containing focal adhesions, more complex actin-cytoskeletal rearrangements, and increased levels of total β1-integrin, c-Src, and paxillin. Immunoblot analysis of adhesive cells using site-specific phospho-antibodies demonstrated ARPKD-associated loss of activation of focal adhesion kinase (FAK) by phosphorylation at its autophosphorylation site (Y397); accelerated FAK inhibition by phosphorylation at Y407, S843, and S910; as well as increased activation of c-Src at pY418. Paxillin coimmunoprecipitation analyses suggested that fibrocystin-1 was a component of the normal focal adhesion complex and that actin and fibrocystin-1 were lost from ARPKD complexes.

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