bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021–10–24
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Repetitive Refractory Renal Cyst Infection in Autosomal Dominant Polycystic Kidney Disease for which Renal Transcatheter Arterial Embolization Was Effective in Preventing Recurrence.
  2. VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.
  3. Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells.
  4. β3 adrenergic receptor as potential therapeutic target in ADPKD.
  5. Exocyst complex mediates recycling of internal cilia.
  6. Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants.
  7. Polycystic kidney disease strikes a nerve.
  8. Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases.
  9. Using Paramecium as a Model for Ciliopathies.
  10. Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations.
  11. Serine-Threonine Kinase inhibition as antifibrotic therapy: TGF-β and ROCK inhibitors.
  12. Enhanced Cellular Cryopreservation by Biopolymer-Associated Suppression of RhoA/ROCK Signaling Pathway.
  13. Rho/ROCK Inhibition Promotes TGF-β3-Induced Tenogenic Differentiation in Mesenchymal Stromal Cells.
  14. Molecular Diagnosis and Prenatal Phenotype Analysis of Eight Fetuses With Ciliopathies.
  1. Intern Med. 2021 ;60(20): 3261-3265
    Repetitive Refractory Renal Cyst Infection in Autosomal Dominant Polycystic Kidney Disease for which Renal Transcatheter Arterial Embolization Was Effective in Preventing Recurrence.
    Tatsuya Suwabe, Masahiko Oguro, Yoshifumi Ubara, Daisuke Ikuma, Hiroki Mizuno, Noriko Hayami, Masayuki Yamanouchi, Naoki Sawa.
      Renal cyst infection is a frequent and serious complication of autosomal dominant polycystic kidney disease (ADPKD) that is often difficult to treat and can be fatal. While nephrectomy is the standard therapy for severe refractory renal cyst infection, it can be associated with severe adverse events. We experienced a case of repetitive renal cyst infection in a 58-year-old Japanese man with ADPKD on dialysis. He underwent renal transcatheter arterial embolization (TAE) four months after the last episodes of renal cyst infection, and his renal cyst infection has not recurred since renal TAE. This case suggested that renal TAE is effective for preventing repetitive renal cyst infection.
    Keywords:  ADPKD; cyst infection; infected cyst; polycystic kidney disease; renal transcatheter arterial embolization
    DOI:  https://doi.org/10.2169/internalmedicine.6974-20
  2. FASEB J. 2021 Nov;35(11): e21987
    VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.
    Murali K Yanda, Liudmila Cebotaru.
      Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing. Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl- secretion; after VX-809 treatment, the basolateral membrane co-localization of CFTR increased ~4-fold, accompanied by a decrease of ~2-3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan indicates that CFTR modulators warrant further development as a treatment for ADPKD.
    Keywords:  CFTR; VX-809; absorption; cysts; polycystic kidney disease; secretion
    DOI:  https://doi.org/10.1096/fj.202101315R
  3. Biomed Res Int. 2021 ;2021 1242916
    Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells.
    Que Thanh Thanh Nguyen, Thi Xoan Hoang, Hyunjin Ryu, Kook-Hwan Oh, Jae Young Kim.
      Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by uncontrollable epithelial cell growth, cyst formation, and kidney malfunction. In the present study, we investigated the antiproliferative effects of the treatment with the combination of paclitaxel (PAC) and all-trans retinoic acid (ATRA) on ADPKD epithelial cells. Our results show that the combined treatment with 1 nM PAC and 10 nM ATRA significantly suppressed ADPKD cell proliferation (20%), while the treatment with ATRA or PAC alone had no such effect. Treatment with PAC and ATRA induced cell cycle arrest at the G2/M phase and apoptosis by upregulating p53 and caspase-8 expression and increased the intracellular calcium (Ca2+) level possibly by enhancing Ca2+ uptake via plasma membrane channels. In addition, this treatment suppressed extracellular signal-regulated kinase signaling possibly through mitogen-activated protein kinase phosphatase-1 activation. Thus, the combination of PAC and ATRA can be explored as a potential treatment regimen for ADPKD.
    DOI:  https://doi.org/10.1155/2021/1242916
  4. Physiol Rep. 2021 Oct;9(20): e15058
    β3 adrenergic receptor as potential therapeutic target in ADPKD.
    Giorgia Schena, Monica Carmosino, Samantha Chiurlia, Laura Onuchic, Mauro Mastropasqua, Eugenio Maiorano, Francesco P Schena, Michael J Caplan.
      Autosomal dominant polycystic kidney disease (ADPKD) disrupts renal parenchyma through progressive expansion of fluid-filled cysts. The only approved pharmacotherapy for ADKPD involves the blockade of the vasopressin type 2 receptor (V2R). V2R is a GPCR expressed by a subset of renal tubular cells and whose activation stimulates cyclic AMP (cAMP) accumulation, which is a major driver of cyst growth. The β3-adrenergic receptor (β3-AR) is a GPCR expressed in most segments of the murine nephron, where it modulates cAMP production. Since sympathetic nerve activity, which leads to activation of the β3-AR, is elevated in patients affected by ADPKD, we hypothesize that β3-AR might constitute a novel therapeutic target. We find that administration of the selective β3-AR antagonist SR59230A to an ADPKD mouse model (Pkd1fl/fl ;Pax8rtTA ;TetO-Cre) decreases cAMP levels, producing a significant reduction in kidney/body weight ratio and a partial improvement in kidney function. Furthermore, cystic mice show significantly higher β3-AR levels than healthy controls, suggesting a correlation between receptor expression and disease development. Finally, β3-AR is expressed in human renal tissue and localizes to cyst-lining epithelial cells in patients. Thus, β3-AR is a potentially interesting target for the development of new treatments for ADPKD.
    Keywords:  G protein-coupled receptors; SR59230A; autosomal dominant polycystic kidney disease; β-adrenergic receptors
    DOI:  https://doi.org/10.14814/phy2.15058
  5. Curr Biol. 2021 Oct 19. pii: S0960-9822(21)01323-3. [Epub ahead of print]
    Exocyst complex mediates recycling of internal cilia.
    Félix E Rivera-Molina, Zhiqun Xi, Elena Reales, Bryan Wang, Derek Toomre.
      Primary cilia are slender, cellular antennae that sense extracellular stimuli, and their absence or dysfunction plays a role in numerous human diseases. Prior work has indicated a role of the exocyst tethering complex in cilia biogenesis and maintenance,1-6 with the underlying paradigm that the exocyst targets vesicles to the ciliary base to deliver ciliary cargoes.7-9 However, the role of the exocyst vis-à-vis to primary cilia in living cells and during stimulation is unknown. Herein, using advanced imaging and quantitative analysis reveals that serum stimulation increases the exocyst's localization to cilia by three-fold. This serum-stimulated localization is highly dynamic, and FRAP experiments show that exocysts at the cilia are highly mobile (60%-80%). Super resolution imaging reveals that the xocyst extends past the cilia base to the entire ciliary pocket. To visualize cilia exocytosis, we conducted live cell imaging with pH-sensitive cilia reporters in combination with extracellular pH switching. Strikingly, we observed that an exocyst-positive internal cilia fuses with the cell surface. These live cell results support a novel and dynamic role of the exocyst complex in the delivery of internalized cilia to the cell surface. Moreover, they suggest a novel pathway may be used to recycle primary cilia to the cell surface that engages the exocyst in response to stimuli. This new remarkable plasticity in cilia presence on the surface in response to extracellular stimuli suggest new means to potentially modulate cilia signaling.
    Keywords:  cilia; ciliary pocket.; ciliogenesis; exocyst; exocytosis; recycling
    DOI:  https://doi.org/10.1016/j.cub.2021.09.067
  6. Commun Biol. 2021 Oct 20. 4(1): 1200
    Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants.
    Nastaran Daneshgar, Andrew W Baguley, Peir-In Liang, Fei Wu, Yi Chu, Michael T Kinter, Gloria A Benavides, Michelle S Johnson, Victor Darley-Usmar, Jianhua Zhang, Kung-Sik Chan, Dao-Fu Dai.
      Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.
    DOI:  https://doi.org/10.1038/s42003-021-02730-w
  7. Physiol Rep. 2021 Oct;9(20): e15078
    Polycystic kidney disease strikes a nerve.
    Bo Yang, Steven D Crowley.
      
    Keywords:  polycystic kidney disease; sympathetic nervous system
    DOI:  https://doi.org/10.14814/phy2.15078
  8. Front Neurosci. 2021 ;15 736888
    Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases.
    Soo Mi Ki, Hui Su Jeong, Ji Eun Lee.
      Many neurodegenerative diseases have been associated with defects in primary cilia, which are cellular organelles involved in diverse cellular processes and homeostasis. Several types of glial cells in both the central and peripheral nervous systems not only support the development and function of neurons but also play significant roles in the mechanisms of neurological disease. Nevertheless, most studies have focused on investigating the role of primary cilia in neurons. Accordingly, the interest of recent studies has expanded to elucidate the role of primary cilia in glial cells. Correspondingly, several reports have added to the growing evidence that most glial cells have primary cilia and that impairment of cilia leads to neurodegenerative diseases. In this review, we aimed to understand the regulatory mechanisms of cilia formation and the disease-related functions of cilia, which are common or specific to each glial cell. Moreover, we have paid close attention to the signal transduction and pathological mechanisms mediated by glia cilia in representative neurodegenerative diseases. Finally, we expect that this field of research will clarify the mechanisms involved in the formation and function of glial cilia to provide novel insights and ideas for the treatment of neurodegenerative diseases in the future.
    Keywords:  glia; myelination; nerve regeneration; neurological disease; primary cilia
    DOI:  https://doi.org/10.3389/fnins.2021.736888
  9. Genes (Basel). 2021 Sep 24. pii: 1493. [Epub ahead of print]12(10):
    Using Paramecium as a Model for Ciliopathies.
    Megan Valentine, Judith Van Houten.
      Paramecium has served as a model organism for the studies of many aspects of genetics and cell biology: non-Mendelian inheritance, genome duplication, genome rearrangements, and exocytosis, to name a few. However, the large number and patterning of cilia that cover its surface have inspired extraordinary ultrastructural work. Its swimming patterns inspired exquisite electrophysiological studies that led to a description of the bioelectric control of ciliary motion. A genetic dissection of swimming behavior moved the field toward the genes and gene products underlying ciliary function. With the advent of molecular technologies, it became clear that there was not only great conservation of ciliary structure but also of the genes coding for ciliary structure and function. It is this conservation and the legacy of past research that allow us to use Paramecium as a model for cilia and ciliary diseases called ciliopathies. However, there would be no compelling reason to study Paramecium as this model if there were no new insights into cilia and ciliopathies to be gained. In this review, we present studies that we believe will do this. For example, while the literature continues to state that immotile cilia are sensory and motile cilia are not, we will provide evidence that Paramecium cilia are clearly sensory. Other examples show that while a Paramecium protein is highly conserved it takes a different interacting partner or conducts a different ion than expected. Perhaps these exceptions will provoke new ideas about mammalian systems.
    Keywords:  Paramecium; cilia; ciliate; ciliopathy
    DOI:  https://doi.org/10.3390/genes12101493
  10. Mol Neurobiol. 2021 Oct 19.
    Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations.
    Wedad Alhassen, Yuki Kobayashi, Jessica Su, Brianna Robbins, Henry Nguyen, Thant Myint, Micah Yu, Surya M Nauli, Yumiko Saito, Amal Alachkar.
      The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.
    Keywords:  Activation; Brain; Cilia; Inactivation; Melanin-concentrating hormone; Signaling
    DOI:  https://doi.org/10.1007/s12035-021-02511-w
  11. Rheumatology (Oxford). 2021 Oct 19. pii: keab762. [Epub ahead of print]
    Serine-Threonine Kinase inhibition as antifibrotic therapy: TGF-β and ROCK inhibitors.
    Fabian A Mendoza, Sergio A Jimenez.
      Serine-threonine kinases mediate the phosphorylation of intracellular protein targets, transferring a phosphorus group from an ATP molecule to the specific amino acid residues within the target proteins. Serine-threonine kinases regulate multiple key cellular functions. From this large group of kinases, transforming growth factor beta (TGF-β) through the serine-threonine activity of its receptors and Rho kinase (ROCK) play an important role in the development and maintenance of fibrosis in various human diseases, including systemic sclerosis. In recent years, multiple drugs targeting and inhibiting these kinases, have been developed, opening the possibility of becoming potential antifibrotic agents of clinical value for treating fibrotic diseases. This review analyzes the contribution of TGF- β and ROCK-mediated serine-threonine kinase molecular pathways to the development and maintenance of pathological fibrosis and the potential clinical use of their inhibition.
    Keywords:  ROCK; ROCK inhibitors; Serine-Threonine kinase; TGF-β; TGF-β inhibitors; antifibrotic treatment; fibrosis; kinase inhibitors
    DOI:  https://doi.org/10.1093/rheumatology/keab762
  12. Materials (Basel). 2021 Oct 14. pii: 6056. [Epub ahead of print]14(20):
    Enhanced Cellular Cryopreservation by Biopolymer-Associated Suppression of RhoA/ROCK Signaling Pathway.
    Tae Wook Lee, Gyeong Won Lee, Seonyeong An, Keum-Yong Seong, Jong Soo Lee, Seung Yun Yang.
      With increasing demands on long-term storage of cells, cryopreservation of cells is gaining more importance in cell-based research and applications. Dimethyl sulfoxide (DMSO) is a commonly used chemical cryoprotectant, providing increased cell survival during the freezing process. However, its use is limited in clinical applications due to its low biocompatibility above cryogenic temperatures. Herein, we present a new approach for reducing the use of DMSO in cryopreservation by using biodegradable hyaluronic acids (HAs). By adding HAs into cryoprotectant media containing a low concentration of DMSO, higher cell viability and cell proliferation rate were observed upon thawing after cryopreservation. The HA-supplemented cryopreservation media did not reduce the size of the ice crystal, which significantly influenced cell viability during cell freezing, but decreased the Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) signaling pathway related to apoptosis. The cell-interactive cryoprotectants containing HA can be applied to the development of a new cryoprotectant that reduces the adverse effect of DMSO.
    Keywords:  RhoA/ROCK signaling pathway; cryopreservation; dimethyl sulfoxide (DMSO); hyaluronic acid; polymeric cryoprotectant
    DOI:  https://doi.org/10.3390/ma14206056
  13. Stem Cells Int. 2021 ;2021 8284690
    Rho/ROCK Inhibition Promotes TGF-β3-Induced Tenogenic Differentiation in Mesenchymal Stromal Cells.
    Michaela Melzer, Susanna Schubert, Simon Franz Müller, Joachim Geyer, Alina Hagen, Sabine Niebert, Janina Burk.
      Mesenchymal stromal cells (MSC) represent a promising therapeutic tool for tendon regeneration. Their tenogenic differentiation is crucial for tissue engineering approaches and may support their beneficial effects after cell transplantation in vivo. The transforming growth factor (TGF)-β, signalling via intracellular Smad molecules, is a potent paracrine mediator of tenogenic induction. Moreover, scaffold topography or tendon matrix components induced tenogenesis via activation of the Rho/ROCK cascade, which, however, is also involved in pathological adaptations in extracellular matrix pathologies. The aim of this study was to investigate the interplay of Rho/ROCK and TGF-β3/Smad signalling in tenogenic differentiation in both human and equine MSC. Primary equine and human MSC isolated from adipose tissue were cultured as monolayers or on tendon-derived decellularized scaffolds to evaluate the influence of the ROCK inhibitor Y-27632 on TGF-β3-induced tenogenic differentiation. The MSC were incubated with and without TGF-β3 (10 ng/ml), Y-27632 (10 μM), or both. On day 1 and day 3, the signalling pathway of TGF-β and the actin cytoskeleton were visualized by Smad 2/3 and phalloidin staining, and gene expression of signalling molecules and tendon markers was assessed. ROCK inhibition was confirmed by disruption of the actin cytoskeleton. Activation of Smad 2/3 with nuclear translocation was evident upon TGF-β3 stimulation. Interestingly, this effect was most pronounced with additional ROCK inhibition in both species (p < 0.05 in equine MSC). In line with that, the tendon marker scleraxis showed the strongest upregulation when TGF-β3 and ROCK inhibition were combined (p < 0.05 in human MSC). The regulation pattern of tendon extracellular matrix components and the signalling molecules TGF-β3 and Smad 8 showed differences between human and equine MSC. The obtained results showed that ROCK inhibition promotes the TGF-β3/Smad 2/3 axis, with possible implications for future MSC priming regimes in tendon therapy.
    DOI:  https://doi.org/10.1155/2021/8284690
  14. Front Genet. 2021 ;12 705808
    Molecular Diagnosis and Prenatal Phenotype Analysis of Eight Fetuses With Ciliopathies.
    Yuefang Liu, Hui Wang, Xin Jin, Qixiang Shao, Qiong Pan.
      Human ciliopathies are hereditary conditions caused by variants in ciliary-associated genes. Ciliopathies are often characterized by multiple system defects. However, it is not easy to make a definite diagnosis in the prenatal period only based on the imageology. In this report, eight new prenatal cases from five unrelated families diagnosed with ciliopathies were systematically examined. The clinical manifestations of these fetuses showed such prenatal diagnostic features as occipital encephalocele, and polydactyly and polycystic kidneys. Situs inversus caused by CPLANE1 variant was first reported. In Family 1 and Family 3, homozygous variants of CPLANE1 and NPHP4 caused by consanguineous marriage and uniparental disomy were detected by whole-exome sequencing, respectively. In Family 2, Family 4 and Family 5, compound heterozygotes of TMEM67 and DYNC2H1 including two novel missense variants and one novel nonsense variant were identified. The distribution of pathogenic missense variants along TMEM67 gene mainly clustered in the extracellular cysteine rich region, extracellular area with unknown structure, and the transmembrane regions. Genotype-phenotype relationship between CPLANE1 and TMEM67 genes was concluded. This report describes new clinical manifestations and novel variants in CPLANE1, TMEM67, NPHP4, and DYNC2H1.
    Keywords:  ciliopathies; occipital encephalocele; polycystic kidneys; polydactyly; prenatal clinical phenotype; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fgene.2021.705808
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