scholarly journals JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis

2018 ◽  
Author(s):  
Foteini Patera ◽  
Alex Cudzich-Mardy ◽  
Zhi Huang ◽  
Maria Fragiadaki
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Three Dimensional ◽  
Polycystic Kidney ◽  
Signalling Molecule ◽  
Cyst Lining ◽  
Bowman's Capsule ◽  
Diseased Kidney ◽  
Cystic Growth

ABSTRACTDysregulated JAK/STAT signalling is implicated in polycystic kidney disease, which is a common genetic disease leading to renal failure. However, the mechanisms underlying JAK/STAT-mediated cystogenesis arepoorlyunderstood.TheroleofJAK2wasinvestigated immunohistochemically in a murine model of cystic disease (Pkd1nl/nl). In the normal kidney, JAK2 is restricted to tubular epithelial and vascular cells with lesser staining in bowman’s capsule and is undetectable in the interstitium. By contrast, in the diseased kidney JAK2 appears stronger in cyst-lining cells when compared to normal tubules and appears mislocalised in the interstitium. Given that JAK2 is a major tyrosine kinase activating JAK/STAT, we considered whether its inhibition can attenuate cystic growth in vitro. To assess this we used curcumin, a natural phytochemical, which significantly reduced JAK2 levels and STAT3 activity. Consistently, reduced JAK2/STAT3 activity was correlated with reduced cystic growth of cystic cells in three-dimensional cyst assays. Taken together, our results suggest that JAK2 is a key signalling molecule that functions to inhibit cystic growth in cystic tubular epithelial cells, thus providing the foundation for its development as a novel therapeutic in polycystic kidney disease.

scholarly journals SP007OLIVE LEAF EXTRACT INHIBITS CELLULAR AND CYSTIC GROWTH IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: AN IN VITRO MODEL

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii104-iii104
Author(s):  
Giuseppina Toteda ◽  
Anna Perri ◽  
Donatella Vizza ◽  
Simona Lupinacci ◽  
Antonella La Russa ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Leaf Extract ◽  
In Vitro Model ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Vitro Model ◽  
Cystic Growth

scholarly journals Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner

2020 ◽  
Vol 98 (11) ◽  
pp. 1547-1559
Author(s):  
Wajima Safi ◽  
Andre Kraus ◽  
Steffen Grampp ◽  
Johannes Schödel ◽  
Bjoern Buchholz
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Macrophage Migration Inhibitory Factor ◽  
Macrophage Migration ◽  
Polycystic Kidney ◽  
Tubular Cells ◽  
Cyst Lining ◽  
Cyst Growth

Abstract Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. Key messages • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.

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.

scholarly journals Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Edmund C. Lee ◽  
Tania Valencia ◽  
Charles Allerson ◽  
Annelie Schairer ◽  
Andrea Flaten ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Collecting Duct ◽  
Treatment Options ◽  
Subcutaneous Administration ◽  
Polycystic Kidney ◽  
Short Oligonucleotide ◽  
Mrna Targets ◽  
Stage Renal Disease

Abstract Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD.

scholarly journals Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease

1998 ◽  
Vol 275 (3) ◽  
pp. F387-F394 ◽  
Author(s):  
William E. Sweeney ◽  
Ellis D. Avner
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Epidermal Growth Factor ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Apical Surface ◽  
Polycystic Kidney ◽  
High Affinity ◽  
Epidermal Growth

Evidence from a number of laboratories suggests a potential role for the epidermal growth factor (EGF)-transforming growth factor-α-epidermal growth factor receptor (EGF-R) axis in promoting epithelial hyperplasia and cyst formation in autosomal recessive polycystic kidney disease (ARPKD). As previously reported, in the C57BL-6Jcpk/cpk (CPK), BALB/c-bpk/bpk (BPK), and C3H-orpk/orpk (ORPK) murine models of ARPKD, as well as in human ARPKD and human ADPKD, the EGF-R is mislocated to the apical surface of cystic collecting tubule (CT) epithelial cells. The present studies demonstrate that cells from cystic and control CTs can be isolated and that these cells maintain their in vivo EGF-R phenotype in vitro. Domain-specific high-affinity ligand binding was assessed by standard Scatchard analysis, and selective ligand stimulation of apical vs. basolateral EGF-R in these cells was followed by measurement of receptor autophosphorylation and determination of cell proliferation. These studies demonstrate that in vitro apically expressed EGF-Rs exhibit high-affinity binding for EGF, autophosphorylate in response to EGF, and transmit a mitogenic signal when stimulated by the appropriate ligand.

scholarly journals An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs

2020 ◽  
Vol 21 (12) ◽  
pp. 4537
Author(s):  
Svenja Koslowski ◽  
Camille Latapy ◽  
Pierrïck Auvray ◽  
Marc Blondel ◽  
Laurent Meijer
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
In Vitro Models ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stage Renal Disease ◽  
End Stage

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.

scholarly journals Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease.

1995 ◽  
Vol 43 (8) ◽  
pp. 785-790 ◽  
Author(s):  
M R Ogborn ◽  
S Sareen ◽  
K Tomobe ◽  
H Takahashi ◽  
J F Crocker
Keyword(s):  
Kidney Disease ◽  
Animal Models ◽  
Polycystic Kidney Disease ◽  
Renal Tubule ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Epithelial Phenotype ◽  
Electrolyte Flux ◽  
Cyst Development

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.

Sign in / Sign up

Export Citation Format

Share Document