bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒11‒14
twenty-nine papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Electrophysiological Recordings of the Polycystin Complex in the Primary Cilium of Cultured Mouse IMCD-3 Cell Line.
  2. Autosomal dominant polycystic kidney disease: possibly the least silent cause of chronic kidney disease.
  3. Recent advances in understanding ion transport mechanisms in polycystic kidney disease.
  4. Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease.
  5. Primary Cilia Are Critical Regulators of White Adipose Tissue Expansion.
  6. A new atypical splice mutation in PKD2 leading to autosomal dominant polycystic kidney disease in a Chinese family.
  7. Detection of Autosomal Dominant Polycystic Kidney Disease by Medical Checkup at an Early Stage.
  8. Epidemiological estimates and early detection of polycystic kidney disease by ultrasonographic assessment in Japan.
  9. Role of Primary Cilia in Bone and Cartilage.
  10. Developing a patient-centred tool for pain measurement and evaluation in autosomal dominant polycystic kidney disease.
  11. Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease.
  12. A visible light-controllable Rho kinase inhibitor based on a photochromic phenylazothiazole.
  13. "ADPKD-omics":Determinants of Cyclic AMP Levels in Renal Epithelial Cells.
  14. Primary Cilia and Centrosomes in Neocortex Development.
  15. Endovascular repair of abdominal aortic or iliac artery pathologies in patients with autosomal dominant polycystic kidney disease.
  16. Stromal cells of giant cell tumor of bone show primary cilia in giant cell tumor of bone.
  17. Ift88, but not Kif3a, is required for establishment of the periciliary membrane compartment.
  18. Erratum to: Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.
  19. Editorial: The Cytoskeleton and Cellular Compartmentation: Cilia as Specialized Cellular Domains.
  20. Novel 3D capsule device to restrict kidney volume expansion on polycystic kidney progression: feasibility study in a rat model.
  21. Pan-ROCK and ROCK2 Inhibitors Affect Dexamethasone-Treated 2D- and 3D-Cultured Human Trabecular Meshwork (HTM) Cells in Opposite Manners.
  22. Isolated Polycystic Liver Disease: A Rare Genetic Disorder.
  23. Identification of Regulators for Ciliary Disassembly by a Chemical Screen.
  24. Primary cilium-dependent autophagy in the response to shear stress.
  25. The roles of intraflagellar transport (IFT) protein 25 in mammalian signaling transduction and flagellogenesis.
  26. Ultrasound-activated ciliary bands for microrobotic systems inspired by starfish.
  27. Upregulation of miR-345-5p suppresses cell growth of lung adenocarcinoma by regulating ras homolog family member A (RhoA) and Rho/Rho associated protein kinase (Rho/ROCK) pathway.
  28. Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury.
  29. Roles of RAGE/ROCK1 Pathway in HMGB1-Induced Early Changes in Barrier Permeability of Human Pulmonary Microvascular Endothelial Cell.
  1. Bio Protoc. 2021 Oct 20. 11(20): e4196
    Electrophysiological Recordings of the Polycystin Complex in the Primary Cilium of Cultured Mouse IMCD-3 Cell Line.
    Kotdaji Ha, Markus Delling.
      PC-1 and PC-2 form an ion channel complex called the polycystin complex, which predominantly localizes to a small hair-like organelle called the primary cilium. The polycystin complex permeates cations, K+, Na+, and Ca2+, and has an unusual 1:3 stoichiometry that combines one PC-1 subunit with three PC-2 subunits. However, the small size and shape of primary cilia impose technical challenges to study the polycystin complex in its native environment. In this paper, we describe the methodology to directly record ion channel activity in primary cilia. This method will allow a detailed functional characterization of how mutations within the polycystin complex cause Autosomal Dominant Polycystic Kidney Disease (ADPKD), essential to develop novel therapeutics for this ciliopathy.
    Keywords:  Electrophysiology; Ion channel; PC-1; PC-2; Polycystin complex; Primary cilia
    DOI:  https://doi.org/10.21769/BioProtoc.4196
  2. Clin Kidney J. 2021 Nov;14(11): 2281-2284
    Autosomal dominant polycystic kidney disease: possibly the least silent cause of chronic kidney disease.
    Roser Torra, Maria Vanessa Pérez-Gómez, Mónica Furlano.
      Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but it remains infrequently and inconsistently measured across countries, studies and trials. The study by El-Damanawi et al. integrated a network of ADPKD expert clinicians, pain specialists, researchers and patient representatives from the national UK PKD charity, with the aim of addressing the lack of validated ADPKD-specific pain assessment tools (APATs). The APAT designed by the authors included several pain measurement tools and was tested in ADPKD patients, although further validation through assessment in larger cohorts is needed. Establishing a standardized instrument for pain measurement will ensure that pain is measured and reported in a consistent way to inform decision-making and identify effective interventions aimed at managing pain and minimizing the impact pain has on patients with ADPKD. In this context, the APAT established by the authors is to be warmly welcomed.
    Keywords:  ADPKD; assessment; pain; patient-reported outcome; trials
    DOI:  https://doi.org/10.1093/ckj/sfab132
  3. Clin Sci (Lond). 2021 Nov 12. 135(21): 2521-2540
    Recent advances in understanding ion transport mechanisms in polycystic kidney disease.
    Anastasia V Sudarikova, Valeriia Y Vasileva, Regina F Sultanova, Daria V Ilatovskaya.
      This review focuses on the most recent advances in the understanding of the electrolyte transport-related mechanisms important for the development of severe inherited renal disorders, autosomal dominant (AD) and recessive (AR) forms of polycystic kidney disease (PKD). We provide here a basic overview of the origins and clinical aspects of ARPKD and ADPKD and discuss the implications of electrolyte transport in cystogenesis. Special attention is devoted to intracellular calcium handling by the cystic cells, with a focus on polycystins and fibrocystin, as well as other calcium level regulators, such as transient receptor potential vanilloid type 4 (TRPV4) channels, ciliary machinery, and purinergic receptor remodeling. Sodium transport is reviewed with a focus on the epithelial sodium channel (ENaC), and the role of chloride-dependent fluid secretion in cystic fluid accumulation is discussed. In addition, we highlight the emerging promising concepts in the field, such as potassium transport, and suggest some new avenues for research related to electrolyte handling.
    Keywords:  Electrolyte transport; Ion channels; Kidney; Polycystic Kidney Disease; Renal Physiology; purinergic signaling
    DOI:  https://doi.org/10.1042/CS20210370
  4. Adv Nutr. 2021 Nov 10. pii: nmab131. [Epub ahead of print]
    Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease.
    Lauren Pickel, Ioan-Andrei Iliuta, James Scholey, York Pei, Hoon-Ki Sung.
      Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens including caloric restriction, intermittent fasting, and ketogenic diets hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signalling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.
    Keywords:  ADPKD; beta-hydroxybutyrate; diet; fasting; hereditary kidney disease; ketosis; polycystic kidney; slow progression; time-restricted eating; time-restricted feeding
    DOI:  https://doi.org/10.1093/advances/nmab131
  5. Front Physiol. 2021 ;12 769367
    Primary Cilia Are Critical Regulators of White Adipose Tissue Expansion.
    Keren I Hilgendorf.
      The primary cilium is a microtubule-based cellular protrusion found on most mammalian cell types in diverse tissues. It functions as a cellular antenna to sense and transduce a broad range of signals, including odorants, light, mechanical stimuli, and chemical ligands. This diversity in signals requires cilia to display a context and cell type-specific repertoire of receptors. Recently, primary cilia have emerged as critical regulators of metabolism. The importance of primary cilia in metabolic disease is highlighted by the clinical features of human genetic disorders with dysfunctional ciliary signaling, which include obesity and diabetes. This review summarizes the current literature on the role of primary cilia in metabolic disease, focusing on the importance of primary cilia in directing white adipose tissue expansion during obesity.
    Keywords:  adipogenesis; diabetes; obesity; primary cilia; signaling
    DOI:  https://doi.org/10.3389/fphys.2021.769367
  6. Singapore Med J. 2021 Nov 08.
    A new atypical splice mutation in PKD2 leading to autosomal dominant polycystic kidney disease in a Chinese family.
    Junlin Zhang, Yiting Wang, Yingwang Zhao, Fang Liu.
      INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a very common hereditary renal disorder. Mutations in PKD1 and PKD2, identified as disease-causing genes, cause about 85% and 15% of ADPKD cases, respectively.METHODS: In this study, the mutation analysis of PKD genes was implemented in a Chinese family with suspected ADPKD using targeted clinical exome sequencing (CES). The candidate pathogenic variants were further tested by using Sanger sequencing and validated for co-segregation. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to test abnormal splicing and assess its potential pathogenicity.
    RESULTS: A novel atypical splicing mutation which belongs to unclassified variants (UCVs), IVS6+5G>C, was identified in three family members by CES and was shown to co-segregate only with the affected individuals. RT-PCR reveals the abnormal splicing of exon 6, thus to cause truncating mutation. These findings suggest that the atypical splice site alteration, IVS6+5G>C, in the PKD2 gene is the potential pathogenic mutation leading to ADPKD in the Chinese family.
    CONCLUSION: The data available in this study provided strong evidence that IVS6+5G>C is the potential pathogenic mutation for ADPKD. Meantime, this case also emphasizes the significance of functional analysis of UCVs and genotype-phenotype correlation in ADPKD.
    Keywords:  PKD genes; atypical splice mutation; autoso¬mal dominant polycystic kidney disease; genetic test
    DOI:  https://doi.org/10.11622/smedj.2021162
  7. Cureus. 2021 Oct;13(10): e18595
    Detection of Autosomal Dominant Polycystic Kidney Disease by Medical Checkup at an Early Stage.
    Shohei Fukunaga, Fumika Kamei, Hirotaka Sonoda, Masafumi Oba, Miharu Kawanishi, Masahiro Egawa, Takafumi Ito, Kazuaki Tanabe.
      INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. Although abdominal echography during medical checkup may be effective for the early detection of ADPKD, there are no reports of the early detection of ADPKD during medical checkup. We investigated whether there was a difference in renal function and total kidney volume (TKV) at the time of diagnosis due to differences in diagnostic triggers for ADPKD.METHODS: A total of 34 patients diagnosed with ADPKD between January 1, 2010, and December 31, 2020, at the Department of Nephrology, Shimane University Hospital, were included. The triggers for diagnosis of the renal cyst(s) were usually unintentional findings. These included findings observed upon routine medical checkups, computed tomography, or abdominal echography during examination for other diseases (incidental detection group) and cases referred to our department for renal dysfunction (renal dysfunction group), and "other" group. We compared the renal dysfunction group and the incidental detection group.
    RESULTS: The estimated glomerular filtration rate (eGFR) at diagnosis was significantly higher in the incidental detection group. The TKV was significantly lower in the incidental detection group than in the other group. The number of patients with eGFR > 45 mL/min/1.73 m2, for which tolvaptan was safe and effective, was significantly higher in the incidental detection group than in the renal dysfunction group.
    CONCLUSION: Our study shows that medical checkup enables early detection of ADPKD. This is important because ADPKD may have serious complications. The present study did not examine the age at which abdominal echography screening for the early detection of ADPKD was more useful or cost-effective; thus, further research is needed to ascertain this.
    Keywords:  adpkd; ckd; medical checkup; renal prognosis; tolvaptan
    DOI:  https://doi.org/10.7759/cureus.18595
  8. Med Ultrason. 2021 Nov 10.
    Epidemiological estimates and early detection of polycystic kidney disease by ultrasonographic assessment in Japan.
    Minoru Kobayashi, Takao Kamai.
      AIMS: To estimate the prevalence of autosomal dominant polycystic kidney disease (ADPKD) and provide the evaluation of new ultrasonographic criteria and clinical indicators to help its early detection.MATERIALS AND METHODS: A total of 30750 individuals for health check-up with abdominal ultrasonography (US) were included, in which 231 suspects of ADPKD based on the number of renal cysts were extracted. They were divided into 4 groups by the grade of suspicion (definitive, a strongsuspect, a fair suspect and a weak suspect). Longitudinal data of US and renal function tests were compared between the groups.The estimated prevalence rate was 0.068% from the study subjects. The level of eGFR did not differ between the definitive and suspects, while the annual estimated glomerular filtration ratio (eGFR) decline was significantly larger in the former (p<0.001). The subjects with growing renal cysts showed a larger annual eGFR decline than those without growth (p=0.0324). The proposed cut-off set at the first quartile of the annualized eGFR change efficiently divided the subjects according to the presence of cyst growth (p= 0.027) and the grade of suspicion of ADPKD (p=0.028).
    CONCLUSION: The prevalence rate of ADPKD was higher than the corresponding rate previously reported in Japan (0.025%), suggesting that health check-ups maybe an efficient opportunity to pick up undiagnosed ADPKD. The large annual eGFR decline and the presence of growing cystsmay be feasible indicators to isolate ADPKD and should be introduced into US based screening to facilitate early detectionof ADPKD.
    DOI:  https://doi.org/10.11152/mu-3330
  9. J Dent Res. 2021 Nov 08. 220345211046606
    Role of Primary Cilia in Bone and Cartilage.
    Z Chinipardaz, M Liu, D T Graves, S Yang.
      The primary cilium is a nonmotile microtubule-based organelle in most vertebrate cell types. The primary cilium plays a critical role in tissue development and homeostasis by sensing and transducing various signaling pathways. Ciliary proteins such as intraflagellar transport (IFT) proteins as well as ciliary motor proteins, kinesin and dynein, comprise a bidirectional intraflagellar transport system needed for cilia formation and function. Mutations in ciliary proteins that lead to loss or dysfunction of primary cilia cause ciliopathies such as Jeune syndrome and Ellis-van Creveld syndrome and cause abnormalities in tooth development. These diseases exhibit severe skeletal and craniofacial dysplasia, highlighting the significance of primary cilia in skeletal development. Cilia are necessary for the propagation of hedgehog, transforming growth factor β, platelet-derived growth factor, and fibroblast growth factor signaling during osteogenesis and chondrogenesis. Ablation of ciliary proteins such as IFT80 or IFT20 blocks cilia formation, which inhibits osteoblast differentiation, osteoblast polarity, and alignment and reduces bone formation. Similarly, cilia facilitate chondrocyte differentiation and production of a cartilage matrix. Cilia also play a key role in mechanosensing and are needed for increased bone formation in response to mechanical forces.
    Keywords:  chondrocytes; ciliary proteins; fracture; osteoblasts; skeletal development; tooth development
    DOI:  https://doi.org/10.1177/00220345211046606
  10. Clin Kidney J. 2021 Nov;14(11): 2338-2348
    Developing a patient-centred tool for pain measurement and evaluation in autosomal dominant polycystic kidney disease.
    Ragada El-Damanawi, Michael Lee, Tess Harris, Laura B Cowley, Ingrid Scholtes, Simon Bond, Richard N Sandford, Ian B Wilkinson, Niek F Casteleijn, Marie C Hogan, Fiona E Karet Frankl, Thomas F Hiemstra.
      Background: Pain affects 60% of the autosomal dominant polycystic kidney disease (ADPKD) population. Despite being an early and debilitating symptom, it is poorly characterized and management is suboptimal. This study aimed to develop an ADPKD-specific pain assessment tool (APAT) to facilitate pain research.Methods: Following a systematic review of PATs used in ADPKD studies and against international recommendations for pain trials, our multi-disciplinary team of clinical experts and patients constructed an ADPKD-pain conceptual framework of key pain evaluation themes. We compiled a new APAT covering domains prioritized within our framework using components of questionnaires validated in other chronic pain disorders. The APAT was administered longitudinally within a randomized high-water intake trial (NCT02933268) to ascertain feasibility and provide pilot data on ADPKD pain.
    Results: Thirty-nine ADPKD participants with chronic kidney disease Stages 1-4 provided 129 APAT responses. Each participant completed a median of 3 (range 1-10) assessments. Respondents' mean ± standard deviation age was 47 ± 13 years; 59% (23) were female; and 69% (27) had enlarged kidneys with median time from diagnosis 14.2 (interquartile range 7.0-25.9) years. Pain (52%) and associated analgesic use (29%) were common. Pain severity was associated with increasing age [odds ratio (OR) = 1.07, P = 0.009], female gender (OR = 4.34, P = 0.018), estimated glomerular filtration rate <60 mL/min/1.73 m2 (OR = 5.45, P = 0.021) and hypertension (OR = 12.11, P = 0.007), but not with kidney size (P = 0.23). The APAT achieved good internal consistency (Cronbach's alpha coefficient = 0.91) and test-retest reliability (domain intra-class correlation coefficients ranging from 0.62 to 0.90).
    Conclusions: The APAT demonstrated good acceptability and reliability, and following further validation in a larger cohort could represent an invaluable tool for future ADPKD pain studies.
    Keywords:  ADPKD; analgesia; chronic pain; pain; patient-reported outcomes
    DOI:  https://doi.org/10.1093/ckj/sfaa259
  11. Clin Kidney J. 2021 Nov;14(11): 2420-2427
    Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease.
    Marlene L Nielsen, Mia C Mundt, Dorte L Lildballe, Maria Rasmussen, Lone Sunde, Vicente E Torres, Peter C Harris, Henrik Birn.
      Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects.Methods: The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC ) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin.
    Results: Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system.
    Conclusions: Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.
    Keywords:  ADPKD; cystogenesis; immunohistochemistry; proximal tubule; targeted treatment
    DOI:  https://doi.org/10.1093/ckj/sfab088
  12. Chem Commun (Camb). 2021 Nov 09.
    A visible light-controllable Rho kinase inhibitor based on a photochromic phenylazothiazole.
    Kazuya Matsuo, Sampreeth Thayyil, Mitsuyasu Kawaguchi, Hidehiko Nakagawa, Nobuyuki Tamaoki.
      Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine kinase whose inhibitors are useful for the regulation of the actomyosin system. Here, we developed a photoswitchable ROCK inhibitor based on a phenylazothiazole scaffold. The reversible trans-cis isomerization by visible light stimuli enabled us to manipulate ROCK activities in vitro and in cells.
    DOI:  https://doi.org/10.1039/d1cc04905d
  13. Kidney Int. 2021 Oct 29. pii: S0085-2538(21)00953-4. [Epub ahead of print]
    "ADPKD-omics":Determinants of Cyclic AMP Levels in Renal Epithelial Cells.
    Yash R Mehta, Spencer A Lewis, Kirby T Leo, Lihe Chen, Euijung Park, Viswanathan Raghuram, Chung-Lin Chou, Chin-Rang Yang, Hiroaki Kikuchi, Syed Khundmiri, Brian Poll, Mark A Knepper.
      The regulation of cyclic AMP (cAMP) levels in kidney epithelial cells is important in at least two groups of disorders, namely water balance disorders and autosomal dominant polycystic kidney disease (ADPKD). Focussing on the latter, we review genes that code for proteins that are determinants of cAMP levels in cells. We identify which of these determinants are expressed in the 14 kidney tubule segments using recently published RNA-seq and protein mass spectrometry data ("ADPKD-omics"). This includes G protein-coupled receptors, adenylyl cyclases, cyclic nucleotide phosphodieterases, cAMP transporters, cAMP binding proteins, regulator of G protein signaling (RGS) proteins, G protein-coupled receptor kinases, arrestins, calcium transporters, and calcium binding proteins. In addition, compartmentalized cAMP signaling in the primary cilium is discussed and a specialized database of the proteome of the primary cilium of cultured "IMCD3" cells is provided as an online resource (https://esbl.nhlbi.nih.gov/Databases/CiliumProteome/). Overall, this paper provides a general resource in the form of a curated list of proteins likely to play roles in determination of cAMP levels in kidney epithelial cells and, therefore likely to be determinants of progression of ADPKD.
    Keywords:  RNA-seq; protein mass spectrometry; vaptans; vasopressin
    DOI:  https://doi.org/10.1016/j.kint.2021.10.014
  14. Front Neurosci. 2021 ;15 755867
    Primary Cilia and Centrosomes in Neocortex Development.
    Michaela Wilsch-Bräuninger, Wieland B Huttner.
      During mammalian brain development, neural stem and progenitor cells generate the neurons for the six-layered neocortex. The proliferative capacity of the different types of progenitor cells within the germinal zones of the developing neocortex is a major determinant for the number of neurons generated. Furthermore, the various modes of progenitor cell divisions, for which the orientation of the mitotic spindle of progenitor cells has a pivotal role, are a key parameter to ensure the appropriate size and proper cytoarchitecture of the neocortex. Here, we review the roles of primary cilia and centrosomes of progenitor cells in these processes during neocortical development. We specifically focus on the apical progenitor cells in the ventricular zone. In particular, we address the alternating, dual role of the mother centriole (i) as a component of one of the spindle poles during mitosis, and (ii) as the basal body of the primary cilium in interphase, which is pivotal for the fate of apical progenitor cells and their proliferative capacity. We also discuss the interactions of these organelles with the microtubule and actin cytoskeleton, and with junctional complexes. Centriolar appendages have a specific role in this interaction with the cell cortex and the plasma membrane. Another topic of this review is the specific molecular composition of the ciliary membrane and the membrane vesicle traffic to the primary cilium of apical progenitors, which underlie the ciliary signaling during neocortical development; this signaling itself, however, is not covered in depth here. We also discuss the recently emerging evidence regarding the composition and roles of primary cilia and centrosomes in basal progenitors, a class of progenitors thought to be of particular importance for neocortex expansion in development and evolution. While the tight interplay between primary cilia and centrosomes makes it difficult to allocate independent roles to either organelle, mutations in genes encoding ciliary and/or centrosome proteins indicate that both are necessary for the formation of a properly sized and functioning neocortex during development. Human neocortical malformations, like microcephaly, underpin the importance of primary cilia/centrosome-related processes in neocortical development and provide fundamental insight into the underlying mechanisms involved.
    Keywords:  centrosome; cilia; microcephaly; neocortical development; neural progenitor; radial glia cells; spindle orientation
    DOI:  https://doi.org/10.3389/fnins.2021.755867
  15. Int Angiol. 2021 Nov 09.
    Endovascular repair of abdominal aortic or iliac artery pathologies in patients with autosomal dominant polycystic kidney disease.
    Jiehua Li, Yuan Peng, Xiaolong Zhang, Chenzi Yang, Xin Li, Hao He, Quanming Li, Chang Shu.
      BACKGROUND: This study aims to evaluate the efficacy and safety of endovascular aneurysm repair (EVAR) of abdominal aortic or iliac artery pathologies in patients with autosomal dominant polycystic kidney disease (ADPKD).METHODS: From January 2014 to December 2019, fifteen consecutive patients (13 men, mean age 69.3 years, range 56-82 years) with abdominal aortic or iliac artery pathologies coexisting with ADPKD underwent EVAR in our department. Their general data, perioperative results and follow-up outcomes were retrospectively reviewed and analyzed. RESULTS：Among the fifteen patients, eleven had abdominal aortic aneurysms, one had isolated abdominal aortic dissection and the other three had iliac artery aneurysms. Three patients had thoracic penetrating aortic ulcer and two had intracranial aneurysms as the comorbidities. All patients underwent EVAR with the aorto-iliac pathologies successfully excluded. The average operative time was 171±73 minutes and average contrast volume was 87±12mL. The average follow-up time was 38.4 months (range 6-60). Aorta-bi-iliac stent-grafts were deployed in fourteen patients, while one patient received tubular stent-graft. Two patients underwent simultaneous TEVAR and EVAR, and One underwent EVAR 3 months after TEVAR. One patient was found to have a hematoma at the site of femoral access 3 days after EVAR. One patient was found to have a Type Ib endoleak 5 months after EVAR, and he recovered well with a secondary endovascular intervention. Contrast-induced nephropathy was observed in two patients (13%) post EVAR. Another patient developed renal failure 20 months after EVAR, and was treated with regular hemodialysis. All other patients did not have any reported significant deterioration of renal function during follow-up. No other adverse events, such as death, paraplegia, aneurysm rupture, or open surgery conversion occurred during operation and follow-up.
    CONCLUSIONS: For patients with abdominal aortic or iliac artery diseases coexisting with ADPKD, EVAR had satisfactory mid-term outcomes, without significantly exacerbating the decline of renal function. However, patients with ADPKD might have multiple vascular lesions, especially intracranial aneurysms, which should be paid enough attention in clinical practice.
    DOI:  https://doi.org/10.23736/S0392-9590.21.04692-7
  16. Microsc Res Tech. 2021 Nov 10.
    Stromal cells of giant cell tumor of bone show primary cilia in giant cell tumor of bone.
    Tomás Castiella, Pablo Iruzubieta, Eva Monleón, Mª José Cardiel, Jesús Gómez-Vallejo, Marta Monzón, Mª Concepción Junquera.
      Giant cell tumor of bone (GCTB) is a locally aggressive primary bone neoplasm composed by tumoral stromal cells (SCs) and a reactive component that consists of monocytic/histiocytic cells that give rise by fusion to osteoclast-like multinucleated cells. Recently, specific Histone 3.3 mutations have been demonstrated in SCs of GCTB. Many of the pathways related to bone proliferation and regulation depend on the primary cilium, a microtubule-based organelle that protrudes outside the cell and acts as a sensorial antenna. In the present work, we aimed to study the presence and role of primary cilia in GCTB. Ultrastructural, immunohistochemical, and immunofluorescence studies were performed in order to demonstrate, for the first time, that the primary cilium is located in spindle-shaped SCs of GCTB. Moreover, we showed Hedgehog (Hh) signaling pathway activation in these cells. Hence, primary cilia may play a relevant role in GCTB tumorogenesis through Hh signaling activation in SCs. RESEARCH HIGHLIGHTS: Transmission electron microscopy allows describing and differentiating cellular subpopulations in giant cell tumor of bone (GCTB). The primary cilium is present in some tumoral stromal cells of GCTB. Hedgehog signalling is activated in these cells.
    Keywords:  Hh signaling pathway; giant cell tumor of bone; primary cilium; ultrastructural study
    DOI:  https://doi.org/10.1002/jemt.23976
  17. Biochem Biophys Res Commun. 2021 Nov 01. pii: S0006-291X(21)01498-4. [Epub ahead of print]584 19-25
    Ift88, but not Kif3a, is required for establishment of the periciliary membrane compartment.
    Fruzsina Kotsis, Heike Janusch, Yujie Li, Amandine Viau, Daniel Epting, Albrecht Kramer-Zucker, Gerd Walz, Roland Nitschke, Esben Lorentzen, Athina Ganner, Elke Neumann-Haefelin, E Wolfgang Kuehn, Christopher Boehlke.
      The primary cilium is a sensory organelle at the cell surface with integral functions in cell signaling. It contains a microtubular axoneme that is rooted in the basal body (BB) and serves as a scaffold for the movement of intraflagellar transport (IFT) particles by Kinesin-2 along the cilium. Ift88, a member of the anterograde moving IFT-B1 complex, as well as the Kinesin-2 subunit Kif3a are required for cilia formation. To facilitate signaling, the cilium restricts the access of molecules to its membrane ("ciliary gate"). This is thought to be mediated by cytoskeletal barriers ("subciliary domains") originating from the BB subdistal/distal appendages, the periciliary membrane compartment (PCMC) as well as the transition fibers and zone (TF/TZ). The PCMC is a poorly characterized membrane domain surrounding the ciliary base with exclusion of certain apical membrane proteins. Here we describe that Ift88, but not Kinesin-2, is required for the establishment of the PCMC in MDCK cells. Likewise, in C. elegans mutants of the Ift88 ortholog osm-5 fail to establish the PCMC, while Kinesin-2 deficient osm-3 mutants form PCMCs normally. Furthermore, disruption of IFT-B1 into two subcomplexes, while disrupting ciliogenesis, does not interfere with PCMC formation. Our findings suggest that cilia are not a prerequisite for the formation of the PCMC, and that separate machineries with partially overlapping functions are required for the establishment of each.
    Keywords:  Ciliary pocket; Ift88; Kif3a; Periciliary membrane compartment; Primary cilia
    DOI:  https://doi.org/10.1016/j.bbrc.2021.10.075
  18. Clin Kidney J. 2021 Nov;14(11): 2451
    Erratum to: Founding mutations explains hotspots of polycystic kidney disease in Southern Spain.
    Carmen García Rabaneda, Francisco Perea, María Luz Bellido Díaz, Ana I Morales García, Margarita Martínez Atienza, Lisbeth Sousa Silva, Miguel Ángel García González, Francisco Ruiz-Cabello, Rafael J Esteban de la Rosa.
      [This corrects the article DOI: 10.1093/ckj/sfaa261.].
    DOI:  https://doi.org/10.1093/ckj/sfab141
  19. Front Cell Dev Biol. 2021 ;9 777758
    Editorial: The Cytoskeleton and Cellular Compartmentation: Cilia as Specialized Cellular Domains.
    Francesc R Garcia-Gonzalo, Helena Soares, Susana S Lopes, Takanari Inoue.
      
    Keywords:  cilia signaling; ciliogenesis; ciliopathies; motile/immotile cilia; primary cilia
    DOI:  https://doi.org/10.3389/fcell.2021.777758
  20. J Nephrol. 2021 Nov 10.
    Novel 3D capsule device to restrict kidney volume expansion on polycystic kidney progression: feasibility study in a rat model.
    Kyongtae T Bae, Kanako Kumamoto, Aya Yoshimura, Masanori Kugita, Shigeo Horie, Tamio Yamaguchi, Junu T Bae, Shizuko Nagao.
      BACKGROUND: Cystogenesis in polycystic kidney disease (PKD) is likely accelerated by various renal insults, including crystal deposition, that activate renal tubule obstruction and dilation. We developed a capsule-based device that can be applied to cystic kidneys to restrict tubular lumen dilatation and cyst expansion.METHODS: Kidney capsule devices were designed from computed tomography images of wild-type and Cy/+ rats. Capsule devices were surgically implanted on kidneys in six surgical sessions over a period of 14 months in 7 wild-type rats of 6.5-8 weeks (3 sham operations, 2 right, 2 left) and 6 Cy/+ rats of 6.5 weeks (2 sham, 3 left, 1 bilateral). After surgery, the rats were followed for 5.4-12.4 weeks' growth and sacrificed to retrieve the kidneys. During the follow-up, serum creatinine was measured and retrieved kidneys were weighed. Histological analysis including cystic area measurement and immunohistochemistry was performed.
    RESULTS: Morphometric capsule devices were configured and developed by an image processing technique and produced using a 3D printer. Encapsulated Cy/+ kidneys (n = 5; mean weight 3.64 g) were consistently smaller in size (by 21-36%; p < 0.001) than unencapsulated Cy/+ kidneys (n = 7; mean weight 5.52 g). Encapsulated Cy/+ kidneys (mean %cyst area: 29.4%) showed smaller histological cystic area (by 28-58%; p < 0.001) than unencapsulated Cy/+ kidneys (mean %cyst area 48.6%). Cell proliferation and macrophages were also markedly reduced in encapsulated Cy/+ kidneys, compared to unencapsulated Cy/+ kidneys.
    CONCLUSIONS: We report a pilot feasibility study for the application of a novel morphometric 3D capsule device to the Cy/+ rat model showing restricted kidney volume expansion on polycystic kidney disease progression.
    Keywords:  3D printing; Image-processing; Intervention; Polycystic kidney disease; Rodent experiment
    DOI:  https://doi.org/10.1007/s40620-021-01160-5
  21. Molecules. 2021 Oct 22. pii: 6382. [Epub ahead of print]26(21):
    Pan-ROCK and ROCK2 Inhibitors Affect Dexamethasone-Treated 2D- and 3D-Cultured Human Trabecular Meshwork (HTM) Cells in Opposite Manners.
    Megumi Watanabe, Yosuke Ida, Masato Furuhashi, Yuri Tsugeno, Fumihito Hikage, Hiroshi Ohguro.
      Effects of a pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025 on dexamethasone (DEX)-treated human trabecular meshwork (HTM) cells as a model of steroid-induced glaucoma were investigated. In the presence of Rip or KD025, DEX-treated HTM cells were subjected to permeability analysis of 2D monolayer by transendothelial electrical resistance (TEER) and FITC-dextran permeability, physical properties, size and stiffness analysis (3D), and qPCR of extracellular matrix (ECM), and their modulators. DEX resulted in a significant increase in the permeability, as well as a large and stiff 3D spheroid, and those effects were inhibited by Rip. In contrast, KD025 exerted opposite effects on the physical properties (down-sizing and softening). Furthermore, DEX induced several changes of gene expressions of ECM and their modulators were also modulated differently by Rip and KD025. The present findings indicate that Rip and KD025 induced opposite effects toward 2D and 3D cell cultures of DEX-treated HTM cells.
    Keywords:  3D spheroid cultures; KD025; Rho-associated coiled-coil containing protein kinase (ROCK); dexamethasone; human trabecular meshwork (HTM); ripasudil
    DOI:  https://doi.org/10.3390/molecules26216382
  22. Cureus. 2021 Oct;13(10): e18560
    Isolated Polycystic Liver Disease: A Rare Genetic Disorder.
    Habib Y Aldabbab, Moayad A Hakeem, Fatimah M Alanazi, Mohammed A Asiri, Mohammad F Al Hani, Rahaf I Alshareef, Abeer R Alkahtani, Rahaf F Alfadhli, Lama Y Alharbi, Abdulla A Jan, Mohanned M Alraddadi, Malak Alshammari.
      Polycystic liver disease is a rare clinical condition that causes portal hypertension. It constitutes a group of disorders with liver lesions resulting from abnormal development of the embryological ductal system. Isolated polycystic disease with the absence of polycystic kidney disease is considered a rare condition. We present the case of a 46-year-old man who presented with epigastric pain and episodes of hematemesis. Abdominal examination revealed enlarged liver. He underwent a computed tomography scan that revealed innumerable cystic liver lesions with the presence of ascites. Further investigations confirmed abnormal liver functions and portal hypertension. Physicians need to consider this diagnosis in the appropriate clinical settings. Extensive involvement of the liver may lead to persistent severe symptoms requiring liver transplantation.
    Keywords:  abdominal pain; case report; genetic disorder; hematemesis; polycystic liver disease
    DOI:  https://doi.org/10.7759/cureus.18560
  23. ACS Chem Biol. 2021 Nov 11.
    Identification of Regulators for Ciliary Disassembly by a Chemical Screen.
    Zhijun Dong, Jia Xu, Junmin Pan.
      Cilia are organelles for cellular signaling and motility. They are assembled in G0/G1 and disassembled prior to mitosis. Compared to what is known about ciliary assembly, less is understood about ciliary disassembly. To uncover new mechanisms of ciliary disassembly, we performed an unbiased chemical screen. Chlamydomonas reinhardtii cells were experimentally induced for ciliary disassembly by treatment with sodium pyrophosphate. An FDA approved drug library (HY-L022P-1, MedChemExpress) was used for the screening. Primary screening with further experiments has identified microtubule stabilizer taxanes, CDK4/6 inhibitor abemaciclib and Raf inhibitor dabrafenib being effective in inhibiting ciliary disassembly induced experimentally but also under physiological conditions. In addition, their effects on ciliary disassembly in mammalian cells has also been confirmed. Thus, our studies have not only revealed new mechanisms in ciliary disassembly but also provided new tools for studying ciliary disassembly. These discovered drugs may be used for therapeutic interventions of disorders involving ciliary degeneration such as retinopathies.
    DOI:  https://doi.org/10.1021/acschembio.1c00823
  24. Biochem Soc Trans. 2021 Nov 08. pii: BST20210810. [Epub ahead of print]
    Primary cilium-dependent autophagy in the response to shear stress.
    Etienne Morel, Nicolas Dupont, Patrice Codogno.
      Mechanical forces, such as compression, shear stress and stretching, play major roles during development, tissue homeostasis and immune processes. These forces are translated into a wide panel of biological responses, ranging from changes in cell morphology, membrane transport, metabolism, energy production and gene expression. Recent studies demonstrate the role of autophagy in the integration of these physical constraints. Here we focus on the role of autophagy in the integration of shear stress induced by blood and urine flows in the circulatory system and the kidney, respectively. Many studies highlight the involvement of the primary cilium, a microtubule-based antenna present at the surface of many cell types, in the integration of extracellular stimuli. The cross-talk between the molecular machinery of autophagy and that of the primary cilium in the context of shear stress is revealed to be an important dialog in cell biology.
    Keywords:  macfroautophagy; primary cilium; shear stress
    DOI:  https://doi.org/10.1042/BST20210810
  25. Asian J Androl. 2021 Nov 02.
    The roles of intraflagellar transport (IFT) protein 25 in mammalian signaling transduction and flagellogenesis.
    Yong-Hong Man, Isabella Warmbrunn, Ling Zhang, Zhi-Bing Zhang.
      Cilium, an organelle with a unique proteome and organization, protruding from the cell surface, generally serves as a force generator and signaling compartment. During ciliogenesis, ciliary proteins are synthesized in cytoplasm and transported into cilia by intraflagellar transport (IFT) particles, where the inner counterparts undergo reverse trafficking. The homeostasis of IFT plays a key role in cilial structure assembly and signaling transduction. Much progress has been made on the mechanisms and functions of IFT; however, recent studies have revealed the involvement of IFT particle subunits in organogenesis and spermatogenesis. In this review, we discuss new concepts concerning the molecular functions of IFT protein IFT25 and how its interactions with other IFT particle subunits are involved in mammalian development and fertility.
    Keywords:  IFT25; cilium; hedgehog signaling; intraflagellar transport; spermatogenesis
    DOI:  https://doi.org/10.4103/aja202179
  26. Nat Commun. 2021 Nov 09. 12(1): 6455
    Ultrasound-activated ciliary bands for microrobotic systems inspired by starfish.
    Cornel Dillinger, Nitesh Nama, Daniel Ahmed.
      Cilia are short, hair-like appendages ubiquitous in various biological systems, which have evolved to manipulate and gather food in liquids at regimes where viscosity dominates inertia. Inspired by these natural systems, synthetic cilia have been developed and utilized in microfluidics and microrobotics to achieve functionalities such as propulsion, liquid pumping and mixing, and particle manipulation. Here, we demonstrate ultrasound-activated synthetic ciliary bands that mimic the natural arrangements of ciliary bands on the surface of starfish larva. Our system leverages nonlinear acoustics at microscales to drive bulk fluid motion via acoustically actuated small-amplitude oscillations of synthetic cilia. By arranging the planar ciliary bands angled towards (+) or away (-) from each other, we achieve bulk fluid motion akin to a flow source or sink. We further combine these flow characteristics with a physical principle to circumvent the scallop theorem and realize acoustic-based propulsion at microscales. Finally, inspired by the feeding mechanism of a starfish larva, we demonstrate an analogous microparticle trap by arranging + and - ciliary bands adjacent to each other.
    DOI:  https://doi.org/10.1038/s41467-021-26607-y
  27. Chin Med J (Engl). 2021 Oct 14. 134(21): 2619-2628
    Upregulation of miR-345-5p suppresses cell growth of lung adenocarcinoma by regulating ras homolog family member A (RhoA) and Rho/Rho associated protein kinase (Rho/ROCK) pathway.
    Qiao-Yun Zhou, Shu-Yu Gui, Peng Zhang, Mei Wang.
      BACKGROUND: Microribose nucleic acids (miRNAs) are implicated in the progression of lung adenocarcinoma. MicroRNA-345-5p (miR-345-5p) is a recently identified anti-oncogene in some human cancers, but its functional role and possible molecular mechanism in lung adenocarcinoma remain unknown. This study aimed to identify the biological function and underlying mechanism of miR-345-5p in lung adenocarcinoma cells.METHODS: In this study, lung adenocarcinoma tissues and adjacent tissues were collected in the First Affiliated Hospital of Anhui Medical University between April 2016 and February 2017. The expression of miR-345-5p and ras homolog family member A (RhoA) in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines (A549, H1650, PC-9, and H441) was detected by reverse transcription quantitative polymerase chain reaction analysis. Functional assays including colony formation, flow cytometry analysis, wound healing, and transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of lung adenocarcinoma cells. In addition, RNA pulldown and luciferase reporter assays were conducted to evaluate the relationship between miR-345-5p and RhoA. Difference between the two groups was analyzed with Student's t test, while that among multiple groups was analyzed with one-way analysis of variance.
    RESULTS: MiR-345-5p expression displayed lower level in lung adenocarcinoma tissues (0.241 ± 0.095 vs.1.000 ± 0.233, t = 19.247, P < 0.001) and cell lines (F = 56.992, P < 0.001) than control tissues and cells. Functional experiments demonstrated that upregulation of miR-345-5p inhibited the malignant phenotypes of lung adenocarcinoma cells via suppressing cell proliferation, migration, invasion, and facilitating cell apoptosis. Additionally, RhoA was verified to be the downstream target of miR-345-5p. Expression of RhoA was downregulated by overexpression of miR-345-5p in PC-9 (0.321 ± 0.047 vs. 1.000 ± 0.127, t = 8.536, P < 0.001) and H1650 (0.398 ± 0.054 vs. 1.000 ± 0.156, t = 4.429, P = 0.011) cells. Rescue assays revealed that overexpression of RhoA rescued the suppressive effects of miR-345-5p upregulation on proliferation, migration, and invasion of lung adenocarcinoma cells. Further, miR-345-5p was found to regulate the Rho/Rho-associated protein kinase (ROCK) signaling pathway by downregulation of RhoA in lung adenocarcinoma cells.
    CONCLUSIONS: MiR-345-5p plays a tumor suppressor role in lung adenocarcinoma cells by downregulating RhoA to inactivate the Rho/ROCK pathway.
    DOI:  https://doi.org/10.1097/CM9.0000000000001804
  28. Int J Mol Sci. 2021 Oct 26. pii: 11573. [Epub ahead of print]22(21):
    Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury.
    Tetsu Kimura, Yuta Horikoshi, Chika Kuriyagawa, Yukitoshi Niiyama.
      Ischemic strokes (IS) and spinal cord injuries (SCI) are major causes of disability. RhoA is a small GTPase protein that activates a downstream effector, ROCK. The up-regulation of the RhoA/ROCK pathway contributes to neuronal apoptosis, neuroinflammation, blood-brain barrier dysfunction, astrogliosis, and axon growth inhibition in IS and SCI. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), were previously considered to be non-functional. However, they have attracted much attention because they play an essential role in regulating gene expression in physiological and pathological conditions. There is growing evidence that ROCK inhibitors, such as fasudil and VX-210, can reduce injury in IS and SCI in animal models and clinical trials. Recently, it has been reported that miRNAs are decreased in IS and SCI, while lncRNAs are increased. Inhibiting the Rho/ROCK pathway with miRNAs alleviates apoptosis, neuroinflammation, oxidative stress, and axon growth inhibition in IS and SCI. Further studies are required to explore the significance of ncRNAs in IS and SCI and to establish new strategies for preventing and treating these devastating diseases.
    Keywords:  Rho; Rho kinase; angiogenesis; apoptosis; axon regrowth; inflammation; neurogenesis; noncoding RNA; spinal cord injury; stroke
    DOI:  https://doi.org/10.3390/ijms222111573
  29. Front Immunol. 2021 ;12 697071
    Roles of RAGE/ROCK1 Pathway in HMGB1-Induced Early Changes in Barrier Permeability of Human Pulmonary Microvascular Endothelial Cell.
    Meng-Jiao Zhao, Hao-Ran Jiang, Jing-Wen Sun, Zi-Ang Wang, Bo Hu, Cheng-Rui Zhu, Xiao-Han Yin, Ming-Ming Chen, Xiao-Chun Ma, Wei-Dong Zhao, Zheng-Gang Luan.
      Background: High mobility group box 1 (HMGB1) causes microvascular endothelial cell barrier dysfunction during acute lung injury (ALI) in sepsis, but the mechanisms have not been well understood. We studied the roles of RAGE and Rho kinase 1 (ROCK1) in HMGB1-induced human pulmonary endothelial barrier disruption.Methods: In the present study, the recombinant human high mobility group box 1 (rhHMGB1) was used to stimulate human pulmonary microvascular endothelial cells (HPMECs). The endothelial cell (EC) barrier permeability was examined by detecting FITC-dextran flux. CCK-8 assay was used to detect cell viability under rhHMGB1 treatments. The expression of related molecules involved in RhoA/ROCK1 pathway, phosphorylation of myosin light chain (MLC), F-actin, VE-cadherin and ZO-1 of different treated groups were measured by pull-down assay, western blot and immunofluorescence. Furthermore, we studied the effects of Rho kinase inhibitor (Y-27632), ROCK1/2 siRNA, RAGE-specific blocker (FPS-ZM1) and RAGE siRNA on endothelial barrier properties to elucidate the related mechanisms.
    Results: In the present study, we demonstrated that rhHMGB1 induced EC barrier hyperpermeability in a dose-dependent and time-dependent manner by measuring FITC-dextran flux, a reflection of the loss of EC barrier integrity. Moreover, rhHMGB1 induced a dose-dependent and time-dependent increases in paracellular gap formation accompanied by the development of stress fiber rearrangement and disruption of VE-cadherin and ZO-1, a phenotypic change related to increased endothelial contractility and endothelial barrier permeability. Using inhibitors and siRNAs directed against RAGE and ROCK1/2, we systematically determined that RAGE mediated the rhHMGB1-induced stress fiber reorganization via RhoA/ROCK1 signaling activation and the subsequent MLC phosphorylation in ECs.
    Conclusion: HMGB1 is capable of disrupting the endothelial barrier integrity. This study demonstrates that HMGB1 activates RhoA/ROCK1 pathway via RAGE, which phosphorylates MLC inducing stress fiber formation at short time, and HMGB1/RAGE reduces AJ/TJ expression at long term independently of RhoA/ROCK1 signaling pathway.
    Keywords:  barrier permeability; endothelium; high mobility group box 1; inflammation; signaling
    DOI:  https://doi.org/10.3389/fimmu.2021.697071
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