bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–09–25
fiveteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Anesthetic Considerations for a Patient with Autosomal Dominant Polycystic Kidney Disease, Having a Ruptured Intracranial Aneurysm for Endovascular Coiling: A Case Report.
  2. Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.
  3. Structure of Motile Cilia.
  4. Utilizing the same incision for staged renal transplant in patients with polycystic kidney disease requiring hand-assisted laparoscopic nephrectomy.
  5. Golgi Dysfunctions in Ciliopathies.
  6. Sugar, sugar: Glucose activates motion in pancreatic cilia.
  7. Primary Cilia Influence Progenitor Function during Cortical Development.
  8. Islet primary cilia motility controls insulin secretion.
  9. Lysophosphatidylinositol Induced Morphological Changes and Stress Fiber Formation through the GPR55-RhoA-ROCK Pathway.
  10. Inhibition of intraflagellar transport protein-88 promotes epithelial-to-mesenchymal transition and reduces cardiac remodeling post-myocardial infarction.
  11. Computational Modeling of Motile Cilia-Driven Cerebrospinal Flow in the Brain Ventricles of Zebrafish Embryo.
  12. Cilia make connections.
  13. Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery.
  14. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.
  15. The KIDNEYCODE Program: Diagnostic Yield and Clinical Features of Individuals with CKD.
  1. Asian J Neurosurg. 2022 Jun;17(2): 379-382
    Anesthetic Considerations for a Patient with Autosomal Dominant Polycystic Kidney Disease, Having a Ruptured Intracranial Aneurysm for Endovascular Coiling: A Case Report.
    Shalvi Mahajan, Vidhya Narayanan, Vikas Bhatia, Vinitha Narayan.
      Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder affecting 1 in 1,000 people worldwide. Intracranial aneurysms are an important extrarenal complication with a prevalence of 9 to 12%. The definitive management of an aneurysm includes surgical clipping or endovascular coiling. There is a paucity of literature regarding the anesthetic management of such patients. The pre-existing renal condition is an additional challenge in the management of these patients as the complications associated with chronic kidney disease are superimposed on those due to subarachnoid hemorrhage. Here, we describe anesthetic management of a patient with ADPKD who had a ruptured anterior communicating artery aneurysm, for which endovascular coiling was done.
    Keywords:  autosomal dominant polycystic kidney disease (ADPKD); cerebrovascular aneurysm; endovascular coiling
    DOI:  https://doi.org/10.1055/s-0042-1750811
  2. Front Mol Biosci. 2022 ;9 981963
    Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.
    Xia Zhou, Vicente E Torres.
      Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3',5'-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.
    Keywords:  ADPKD (autosomal dominant polycystic kidney disease); PKD; cAMP signaling; protein kinase A (PKA); tolvaptan; vassopressin
    DOI:  https://doi.org/10.3389/fmolb.2022.981963
  3. Subcell Biochem. 2022 ;99 471-494
    Structure of Motile Cilia.
    Takashi Ishikawa.
      Cilia are tail-like organelles responsible for motility, transportation, and sensory functions in eukaryotic cells. Cilia research has been providing multifaceted questions, attracting biologists of various areas and inducing interdisciplinary studies. In this chapter, we mainly focus on efforts to elucidate the molecular mechanism of ciliary beating motion, a field of research that has a long history and is still ongoing. We also overview topics closely related to the motility mechanism, such as ciliogenesis, cilia-related diseases, and sensory cilia. Subnanometer-scale to submillimeter-scale 3D imaging of the axoneme and the basal body resulted in a wide variety of insights into these questions.
    Keywords:  Axoneme; Basal body; Centriole; Cilia; Cryo-EM; Cryo-ET; Dynein; Electron tomography; Flagella; Microtubule
    DOI:  https://doi.org/10.1007/978-3-031-00793-4_15
  4. ANZ J Surg. 2022 Sep 20.
    Utilizing the same incision for staged renal transplant in patients with polycystic kidney disease requiring hand-assisted laparoscopic nephrectomy.
    Nguyen Huynh, Peter Yoon, Amy Hort, Jinna Yao, Taina Lee, Lawrence Yuen, Jerome Martin Laurence, Henry Pleass.
       BACKGROUNDS: Many autosomal dominant polycystic kidney disease (ADPKD) patients undergo nephrectomy and subsequent renal transplantation. We report our outcomes after hand-assisted laparoscopic nephrectomy (HALN) where a Rutherford-Morrison incision is used as a hand-port site and kidney extraction site, as well the future incision site for staged transplantation.
    METHODS: A retrospective review was performed on all adult nephrectomies for ADPKD by the Transplant Surgery department at Westmead Hospital between June 2011 and June 2021. Outcomes were compared between HALN, laparoscopic nephrectomy (LN) and open nephrectomy (ON) including operation time, hospital length of stay (LOS), post-operative complications, subsequent transplantation and post-transplantation wound complications.
    RESULTS: Twenty-two HALN, 8 LN and 5 ON were performed during the study period. Median kidney weights for HALN, LN and ON were significantly different (1575, 403, 3420 g respectively, P = 0.001). There was a significant difference in LOS between the HALN and ON (5.8 versus 9.8 days, P = 0.04), but not between HALN and LN (5.8 versus 5.1, P = 0.06). There was no significant difference for operation time (P = 0.34) and major complication rates (P = 0.58). There were 8 HALN, 5 LN and 2 ON who have had subsequent renal transplantation with one wound complication, an incisional hernia in the HALN group.
    CONCLUSION: Our HALN is associated with a shorter LOS and similar complication rate to ON and can be efficiently performed for significantly larger kidneys than LN without a significant difference in operation time or LOS. The same Rutherford-Morrison incision site can be used for transplantation.
    Keywords:  nephrectomy; polycystic kidney disease; transplantation
    DOI:  https://doi.org/10.1111/ans.18038
  5. Cells. 2022 Sep 06. pii: 2773. [Epub ahead of print]11(18):
    Golgi Dysfunctions in Ciliopathies.
    Justine Masson, Vincent El Ghouzzi.
      The Golgi apparatus (GA) is essential for intracellular sorting, trafficking and the targeting of proteins to specific cellular compartments. Anatomically, the GA spreads all over the cell but is also particularly enriched close to the base of the primary cilium. This peculiar organelle protrudes at the surface of almost all cells and fulfills many cellular functions, in particular during development, when a dysfunction of the primary cilium can lead to disorders called ciliopathies. While ciliopathies caused by loss of ciliated proteins have been extensively documented, several studies suggest that alterations of GA and GA-associated proteins can also affect ciliogenesis. Here, we aim to discuss how the loss-of-function of genes coding these proteins induces ciliary defects and results in ciliopathies.
    Keywords:  Golgi; Golgipathies; ciliopathy; genetic screening; primary cilium
    DOI:  https://doi.org/10.3390/cells11182773
  6. Sci Adv. 2022 Sep 23. 8(38): eade4450
    Sugar, sugar: Glucose activates motion in pancreatic cilia.
    Haixin Sui.
      Pancreatic primary cilia are active and dynamic, not static antenna-like sensors as previously thought. This movement may be an important mechanism to glucose regulation.
    DOI:  https://doi.org/10.1126/sciadv.ade4450
  7. Cells. 2022 Sep 16. pii: 2895. [Epub ahead of print]11(18):
    Primary Cilia Influence Progenitor Function during Cortical Development.
    Donia Zaidi, Kaviya Chinnappa, Fiona Francis.
      Corticogenesis is an intricate process controlled temporally and spatially by many intrinsic and extrinsic factors. Alterations during this important process can lead to severe cortical malformations. Apical neuronal progenitors are essential cells able to self-amplify and also generate basal progenitors and/or neurons. Apical radial glia (aRG) are neuronal progenitors with a unique morphology. They have a long basal process acting as a support for neuronal migration to the cortical plate and a short apical process directed towards the ventricle from which protrudes a primary cilium. This antenna-like structure allows aRG to sense cues from the embryonic cerebrospinal fluid (eCSF) helping to maintain cell shape and to influence several key functions of aRG such as proliferation and differentiation. Centrosomes, major microtubule organising centres, are crucial for cilia formation. In this review, we focus on how primary cilia influence aRG function during cortical development and pathologies which may arise due to defects in this structure. Reporting and cataloguing a number of ciliary mutant models, we discuss the importance of primary cilia for aRG function and cortical development.
    Keywords:  cortical development; cortical malformations; neuronal progenitors; primary cilia
    DOI:  https://doi.org/10.3390/cells11182895
  8. Sci Adv. 2022 Sep 23. 8(38): eabq8486
    Islet primary cilia motility controls insulin secretion.
    Jung Hoon Cho, Zipeng A Li, Lifei Zhu, Brian D Muegge, Henry F Roseman, Eun Young Lee, Toby Utterback, Louis G Woodhams, Philip V Bayly, Jing W Hughes.
      Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here, we show that primary cilia in human and mouse pancreatic islets exhibit movement that is required for glucose-dependent insulin secretion. Islet primary cilia contain motor proteins conserved from those found in classic motile cilia, and their three-dimensional motion is dynein-driven and dependent on adenosine 5'-triphosphate and glucose metabolism. Inhibition of cilia motion blocks beta cell calcium influx and insulin secretion. Human beta cells have enriched ciliary gene expression, and motile cilia genes are altered in type 2 diabetes. Our findings redefine primary cilia as dynamic structures having both sensory and motile function and establish that pancreatic islet cilia movement plays a regulatory role in insulin secretion.
    DOI:  https://doi.org/10.1126/sciadv.abq8486
  9. Int J Mol Sci. 2022 Sep 18. pii: 10932. [Epub ahead of print]23(18):
    Lysophosphatidylinositol Induced Morphological Changes and Stress Fiber Formation through the GPR55-RhoA-ROCK Pathway.
    Keisuke Nakajima, Saori Oka, Takashi Tanikawa, Yoko Nemoto-Sasaki, Naoki Matsumoto, Hiroki Ishiguro, Yoichiro Arata, Takayuki Sugiura, Atsushi Yamashita.
      We previously reported that lysophosphatidylinositol (LPI) functions as an endogenous agonist of GPR55, a novel cannabinoid receptor. However, the physiological roles of LPI-GPR55 have not yet been elucidated in detail. In the present study, we found that LPI induced morphological changes in GPR55-expressing HEK293 cells. LPI induced the cell rounding of GPR55-expressing HEK293 cells but not of empty-vector-transfected cells. LPI also induced the activation of small GTP-binding protein RhoA and increased stress fiber formation in GPR55-expressing HEK293 cells. The inhibition of RhoA and Rho kinase ROCK by the C3 exoenzyme and the ROCK inhibitor reduced LPI-induced cell rounding and stress fiber formation. These results clearly indicated that the LPI-induced morphological changes and the assembly of the cytoskeletons were mediated through the GPR55-RhoA-ROCK pathway.
    Keywords:  G12/13-RhoA-ROCK pathway; GPR55; endocannabinoid; lysophosphatidylinositol; lysophospholipid mediator; morphological change
    DOI:  https://doi.org/10.3390/ijms231810932
  10. Eur J Pharmacol. 2022 Sep 20. pii: S0014-2999(22)00548-9. [Epub ahead of print] 175287
    Inhibition of intraflagellar transport protein-88 promotes epithelial-to-mesenchymal transition and reduces cardiac remodeling post-myocardial infarction.
    Jessica N Blom, Xiaoyan Wang, Xiangru Lu, Mella Y Kim, Guoping Wang, Qingping Feng.
      The epicardium is a potential source of cardiac progenitors to support reparative angiogenesis after myocardial infarction (MI) through epithelial-to-mesenchymal transition (EMT). Primary cilia are recognized as hubs of cellular signaling, and their presence can alter downstream pathways to modulate EMT. The present study aimed to examine the effects of inhibiting intraflagellar transport protein-88 (Ift88), a protein vital to ciliary assembly on epicardial EMT and cardiac remodeling post-MI. Epicardium derived cells (EPDCs) were cultured from E13.5 heart explants and treated with adenoviral vector encoding short-hairpin RNA against the mouse Ift88 (Ad-shIft88) to disassemble the primary cilium. Effects of Ad-shIft88 on epicardial EMT and cardiac remodeling were examined in mice post-MI. Our results show that Ad-shIft88 enhanced EMT of cultured EPDCs. In adult mice, intra-myocardial administration of Ad-shIft88 increased the number of Wilms' tumor 1 (Wt1) positive cells in the epicardium and myocardium, promoted expression of genes associated with epicardial EMT, and enhanced capillary and arteriolar densities post-MI. Additionally, intra-myocardial Ad-shIft88 treatment attenuated cardiac hypertrophy and improved myocardial function three weeks post-MI. In conclusion, knockdown of Ift88 improves epicardial EMT, neovascularization and cardiac remodeling in the ischemic heart. Our study highlights the primary cilium as a potential therapeutic target post-MI.
    Keywords:  Cardiac remodeling; Epithelial-to-mesenchymal transition; Myocardial infarction; Primary cilium
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175287
  11. Bioengineering (Basel). 2022 Aug 28. pii: 421. [Epub ahead of print]9(9):
    Computational Modeling of Motile Cilia-Driven Cerebrospinal Flow in the Brain Ventricles of Zebrafish Embryo.
    Huseyin Enes Salman, Nathalie Jurisch-Yaksi, Huseyin Cagatay Yalcin.
      Motile cilia are hair-like microscopic structures which generate directional flow to provide fluid transport in various biological processes. Ciliary beating is one of the sources of cerebrospinal flow (CSF) in brain ventricles. In this study, we investigated how the tilt angle, quantity, and phase relationship of cilia affect CSF flow patterns in the brain ventricles of zebrafish embryos. For this purpose, two-dimensional computational fluid dynamics (CFD) simulations are performed to determine the flow fields generated by the motile cilia. The cilia are modeled as thin membranes with prescribed motions. The cilia motions were obtained from a two-day post-fertilization zebrafish embryo previously imaged via light sheet fluorescence microscopy. We observed that the cilium angle significantly alters the generated flow velocity and mass flow rates. As the cilium angle gets closer to the wall, higher flow velocities are observed. Phase difference between two adjacent beating cilia also affects the flow field as the cilia with no phase difference produce significantly lower mass flow rates. In conclusion, our simulations revealed that the most efficient method for cilia-driven fluid transport relies on the alignment of multiple cilia beating with a phase difference, which is also observed in vivo in the developing zebrafish brain.
    Keywords:  ANSYS; brain ventricles; cerebrospinal flow; computational fluid dynamics; embryonic development; motile cilia; zebrafish
    DOI:  https://doi.org/10.3390/bioengineering9090421
  12. Nat Rev Neurosci. 2022 Sep 21.
    Cilia make connections.
    Katherine Whalley.
      
    DOI:  https://doi.org/10.1038/s41583-022-00636-y
  13. Sci Adv. 2022 Sep 23. 8(38): eabq0866
    Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery.
    Ken Hiratsuka, Tomoya Miyoshi, Katharina T Kroll, Navin R Gupta, M Todd Valerius, Thomas Ferrante, Michifumi Yamashita, Jennifer A Lewis, Ryuji Morizane.
      Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration-approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.
    DOI:  https://doi.org/10.1126/sciadv.abq0866
  14. Cell Death Dis. 2022 Sep 20. 13(9): 806
    Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.
    Lena Blümel, Nan Qin, Johannes Berlandi, Eunice Paisana, Rita Cascão, Carlos Custódia, David Pauck, Daniel Picard, Maike Langini, Kai Stühler, Frauke-Dorothee Meyer, Sarah Göbbels, Bastian Malzkorn, Max C Liebau, João T Barata, Astrid Jeibmann, Kornelius Kerl, Serap Erkek, Marcel Kool, Stefan M Pfister, Pascal D Johann, Michael C Frühwald, Arndt Borkhardt, Guido Reifenberger, Claudia C Faria, Ute Fischer, Martin Hasselblatt, Jasmin Bartl, Marc Remke.
      Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-022-05243-4
  15. Kidney360. 2022 May 26. 3(5): 900-909
    The KIDNEYCODE Program: Diagnostic Yield and Clinical Features of Individuals with CKD.
    Kenneth V Lieberman, Alexander R Chang, Geoffrey A Block, Kristina Robinson, Sara L Bristow, Ana Morales, Asia Mitchell, Stephen McCalley, Jim McKay, Martin R Pollak, Swaroop Aradhya, Bradley A Warady.
       Background: Despite increasing recognition that CKD may have underlyi ng genetic causes, genetic testing remains limited. This study evaluated the diagnostic yield and phenotypic spectrum of CKD in individuals tested through the KIDNEYCODE sponsored genetic testing program.
    Methods: Unrelated individuals who received panel testing (17 genes) through the KIDNEYCODE sponsored genetic testing program were included. Individuals had to meet at least one of the following eligibility criteria: eGFR ≤90 ml/min per 1.73m2 and hematuria or a family history of kidney disease; or suspected/biopsy-confirmed Alport syndrome or FSGS in tested individuals or relatives.
    Results: Among 859 individuals, 234 (27%) had molecular diagnoses in genes associated with Alport syndrome (n=209), FSGS (n=12), polycystic kidney disease (n=6), and other disorders (n=8). Among those with positive findings in a COL4A gene, the majority were in COL4A5 (n=157, 72 hemizygous male and 85 heterozygous female individuals). A positive family history of CKD, regardless of whether clinical features were reported, was more predictive of a positive finding than was the presence of clinical features alone. For the 248 individuals who had kidney biopsies, a molecular diagnosis was returned for 49 individuals (20%). Most (n=41) individuals had a molecular diagnosis in a COL4A gene, 25 of whom had a previous Alport syndrome clinical diagnosis, and the remaining 16 had previous clinical diagnoses including FSGS (n=2), thin basement membrane disease (n=9), and hematuria (n=1). In total, 491 individuals had a previous clinical diagnosis, 148 (30%) of whom received a molecular diagnosis, the majority (89%, n=131) of which were concordant.
    Conclusions: Although skewed to identify individuals with Alport syndrome, these findings support the need to improve access to genetic testing for patients with CKD-particularly in the context of family history of kidney disease, hematuria, and hearing loss.
    Keywords:  Alport syndrome; CKD; FSGS; PKD; eGFR; genetic testing; genetics; hematuria; kidney biopsy
    DOI:  https://doi.org/10.34067/KID.0004162021
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