K Homology Domains of the Mouse Polycystic Kidney Disease-Related Protein, Bicaudal-C (Bicc1), Mediate RNA Binding in vitro

2008 ◽  
Vol 108 (1) ◽  
pp. e27-e34 ◽  
Author(s):  
Denise J. Bouvrette ◽  
Sarah J. Price ◽  
Elizabeth C. Bryda
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Rna Binding ◽  
Related Protein ◽  
Polycystic Kidney ◽  
Homology Domains

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.

scholarly journals Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease.

1993 ◽  
Vol 41 (4) ◽  
pp. 555-558 ◽  
Author(s):  
M R Ogborn ◽  
S Sareen ◽  
P C Grimm
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Fluid Transport ◽  
Cyst Formation ◽  
In Vivo Studies ◽  
High Threshold ◽  
Polycystic Kidney ◽  
C3h Mice

Cyst formation in polycystic kidney disease (PKD) involves proliferation of cyst lining epithelial and changes in trans-epithelial fluid and electrolyte transport. In vitro studies have suggested that mislocation of Na,K-ATPase to the apical tubular surface may be an important component of cyst fluid transport. We undertook in vivo studies of Na,K-ATPase location using the "threshold" murine model of glucocorticoid-induced PKD (GIPKD). Using histological, immunohistochemical, and densitometric techniques, we compared cyst formation and the cellular location of Na,K-ATPase in suckling C3H (low threshold for GIPKD) and DBA (high threshold) mice given an inducing dose of 200 mg/kg methylprednisolone acetate. As expected, C3H mice demonstrated greater cyst formation as measured by proportion of section area occupied by the tubule lumen (26.7% vs 15.5%; p < 0.001). Cyst formation was associated with increased Na,K-ATPase staining and increased apical Na,K-ATPase location. MPA treatment in C3H mice resulted in apical staining that exceeded basolateral staining (35.3% of reference window vs 29.8%; p < 0.001). The relatively GIPKD-resistant DBA mice did not show such change in Na,K-ATPase location. These immunohistochemical studies suggest a role for Na,K-ATPase in renal cyst formation.

scholarly journals Establishment of a Ciliogenesis-Associated Signaling Model for Polycystic Kidney Disease

2021 ◽  
pp. 1-9
Author(s):  
Ling Lu ◽  
Qiuling Liu ◽  
Lei Zhi ◽  
Xuchun Che ◽  
Bo Xiao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Differential Expression Analysis ◽  
Valuable Insight ◽  
Polycystic Kidney ◽  
Hub Genes ◽  
Zebrafish Model

<b><i>Background:</i></b> Polycystic kidney disease (PKD) represents the most prevalent inherited progressive kidney disorder in humans. Due to complexity of the genetic network behind the disease, the molecular mechanisms of PKD are still poorly understood yet. <b><i>Objectives:</i></b> This study aimed to develop a ciliogenesis-associated gene network for PKD patients and comprehensively understand the molecular mechanisms underlying the disease. <b><i>Method:</i></b> The potential hub genes were selected based on the differential expression analysis from the GEO database. Meanwhile, the primary hub genes were further elucidated by both in vivo and in vitro experiments. <b><i>Results:</i></b> In this study, we established a comprehensive differentially expressed genes profile (including <i>GNAS, PI4KB, UMOD, SLC7A13,</i> and <i>MIOX</i>) for PKD patients compared with the control specimen. At the same time, enrichment analysis was utilized to demonstrate that the G-protein-related signaling and cilia assembling signaling pathways were closely associated with PKD development. The further investigations of the interaction between 2 genes (<i>GNAS</i> and <i>PI4KB</i>) with in vivo and in vitro analyses revealed that PI4KB functioned as a downstream factor for GNAS and spontaneously activated the phosphorylation of Akt into p-Akt for ciliogenesis in PKD formation. The <i>PI4KB</i> depletion mutant zebrafish model displayed a PKD phenotype as well as absence of primary cilia in the kidney<i>.</i> <b><i>Conclusions:</i></b> Collectively, our work discovered an innovative potential signaling pathway model for PKD formation, which provided a valuable insight for future study of the mechanism of this disease.

scholarly journals Ciclopirox Olamine Induces Ferritinophagy and Ameliorates Disease Progression in Polycystic Kidney Disease

2020 ◽  
Author(s):  
Priyanka S. Radadiya ◽  
Rajni V. Puri ◽  
Brenda Magenheimer ◽  
Dharmalingam Subramaniam ◽  
Pamela V. Tran ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Polycystic Kidney Disease ◽  
Free Acid ◽  
Post Partum ◽  
Weight Ratio ◽  
Collagen Matrix ◽  
Polycystic Kidney ◽  
Cystic Kidneys

Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox, as the free acid (CPX) and its olamine salt (CPX-O) , are contained in number of commercially available topical antifungal agents. CPX is reported in the literature to possess anticancer activity in number of solid tumor cancers and hematological malignancy by several proposed mechanisms of action including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human cyst epithelial cells cultured in 3D collagen matrix. To determine if CPX-O inhibits PKD progression, we treated PKD mice with a low dose of 10 mg/kg CPX-O by daily intraperitoneal injections from day 21 to day 49 post- partum. CPX-O reduced the kidney to body weight ratio of the PKD mice. This was associated with decreased cell proliferation decrease cystic area and improved renal function. We found that ferritin levels were significantly elevated in cystic kidneys of PKD mice, and that CPX-O treatment reduced renal ferritin levels and increased ferritinophagy marker, NCOA4. Our data suggest that CPX-O dose dependently induces ferritin degradation via ferritinophagy which is associated with decreased cyst growth and disease progression in PKD mice. Most importantly these data indicate that CPX-O, a drug used to treat skin infections and currently in clinical trials for cancer, has the potential to treat ADPKD.

scholarly journals The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease

2020 ◽  
Author(s):  
Shirin V. Sundar ◽  
Xia Zhou ◽  
Brenda S. Magenheimer ◽  
Gail A. Reif ◽  
Darren P. Wallace ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Cell Motility ◽  
Polycystic Kidney Disease ◽  
Short Circuit ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Cyst Growth

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50 of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl− channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox:Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl− secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

Sign in / Sign up

Export Citation Format

Share Document