bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–11–13
twenty-two papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Dietary Aspects and Drug-Related Side Effects in Autosomal Dominant Polycystic Kidney Disease Progression.
  2. Recurrent haematospermia: an unusual presentation of autosomal dominant polycystic kidney disease.
  3. Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD).
  4. TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia.
  5. Clinical and genetic study of a Chinese family affected by both amyotrophic lateral sclerosis and autosomal dominant polycystic kidney disease.
  6. Structures and functions of cilia during vertebrate embryo development.
  7. Autosomal dominant polycystic kidney.
  8. Techniques for Visualization and Quantification of Primary Cilia in Chondrocytes.
  9. Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.
  10. Urinary epidermal growth factor/monocyte chemotactic peptide 1 ratio as non-invasive predictor of Mayo clinic imaging classes in autosomal dominant polycystic kidney disease.
  11. The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling.
  12. The apical ciliary adhesion complex is established at the basal foot of motile cilia and depends on the microtubule network.
  13. YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression.
  14. Correction: Cilia regeneration requires an RNA splicing factor from the ciliary base.
  15. Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B.
  16. Effect of Rho-Associated Kinase Inhibitor on Growth Behaviors of Human Induced Pluripotent Stem Cells in Suspension Culture.
  17. Identification of the electrogenic 2Cl-/H+ exchanger, ClC5, as a chloride secreting transporter candidate in kidney cyst epithelium in tuberous sclerosis.
  18. Association of the Urine-to-Plasma Urea Ratio With CKD Progression.
  19. Expression of Concern: FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity.
  20. Transforming growth factor-β1 and bone morphogenetic protein-2 inhibit differentiation into mature ependymal multiciliated cells.
  21. Rethinking the cilia hypothesis of hydrocephalus.
  22. CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signaling to promote expansion of cortical progenitors.
  1. Nutrients. 2022 Nov 03. pii: 4651. [Epub ahead of print]14(21):
    Dietary Aspects and Drug-Related Side Effects in Autosomal Dominant Polycystic Kidney Disease Progression.
    Borja Quiroga, Roser Torra.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. In the absence of targeted therapies, it invariably progresses to advanced chronic kidney disease. To date, the only approved treatment is tolvaptan, a vasopressin V2 receptor antagonist that has been demonstrated to reduce cyst growth and attenuate the decline in kidney function. However, it has various side effects, the most frequent of which is aquaresis, leading to a significant discontinuation rate. The strategies proposed to combat aquaresis include the use of thiazides or metformin and a reduction in the dietary osmotic load. Beyond the prescription of tolvaptan, which is limited to those with a rapid and progressive decline in kidney function, dietary interventions have been suggested to protect against disease progression. Moderate sodium restriction, moderate protein intake (up to 0.8 g/kg/day), avoidance of being overweight, and increased water consumption are recommended in ADPKD guidelines, though all with low-grade evidence. The aim of the present review is to critically summarize the evidence on the effect of dietary modification on ADPKD and to offer some strategies to mitigate the adverse aquaretic effects of tolvaptan.
    Keywords:  aquaresis; autosomal dominant polycystic kidney disease; diet; nutrition; tolvaptan
    DOI:  https://doi.org/10.3390/nu14214651
  2. BMJ Case Rep. 2022 Nov 10. pii: e251868. [Epub ahead of print]15(11):
    Recurrent haematospermia: an unusual presentation of autosomal dominant polycystic kidney disease.
    Vivek Sood, Viswanadh Bhairavabhatla, Somali Pattanayak, Vishal Singh.
      Haematospermia, even though alarming, is usually benign and self-limiting, especially in a sexually active male. Nevertheless recurrent, refractory or painful haematospermia is troublesome and warrants thorough evaluation. In this context, we describe a rare case of recurrent haematospermia whereby evaluation revealed haemorrhage in seminal vesicle cysts and consequently established the aetiology of autosomal dominant polycystic kidney disease.
    Keywords:  Hematuria; Urinary tract infections
    DOI:  https://doi.org/10.1136/bcr-2022-251868
  3. J Clin Med. 2022 Nov 03. pii: 6528. [Epub ahead of print]11(21):
    Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD).
    Akinari Sekine, Sumi Hidaka, Tomofumi Moriyama, Yasuto Shikida, Keiji Shimazu, Eiji Ishikawa, Kiyotaka Uchiyama, Hiroshi Kataoka, Haruna Kawano, Mahiro Kurashige, Mai Sato, Tatsuya Suwabe, Shinya Nakatani, Tadashi Otsuka, Hirayasu Kai, Kan Katayama, Shiho Makabe, Shun Manabe, Wataru Shimabukuro, Koichi Nakanishi, Saori Nishio, Fumihiko Hattanda, Kazushige Hanaoka, Kenichiro Miura, Hiroki Hayashi, Junichi Hoshino, Ken Tsuchiya, Toshio Mochizuki, Shigeo Horie, Ichiei Narita, Satoru Muto.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.
    Keywords:  ADPKD; cystic kidney diseases; differential diagnosis; hereditary
    DOI:  https://doi.org/10.3390/jcm11216528
  4. Biochem Biophys Res Commun. 2022 Oct 27. pii: S0006-291X(22)01489-9. [Epub ahead of print]636(Pt 1): 162-169
    TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia.
    Zhuoma Yinsheng, Ko Miyoshi, Yuanyuan Qin, Yuuki Fujiwara, Takeshi Yoshimura, Taiichi Katayama.
      Primary cilia transduce signals via transmembrane and membrane-associated proteins localized to the ciliary membrane in vertebrate cells. In humans, transmembrane protein 67 (TMEM67), a component of the multiprotein complex functioning as a gatekeeper at the transition zone (TZ) of primary cilia, is mutated in patients suffering from cilia-related pleiotropic diseases, collectively referred to as ciliopathies. The requirement of TMEM67 for the gating function of the TZ that delivers membrane proteins into the ciliary compartment has not been determined. In this study, we established hTERT-RPE1 cells with knockout (KO) of TMEM67 and examined whether cilium formation and TZ gating are affected by its ablation. TMEM67-KO cells displayed impaired ciliogenesis, elongated cilia, perturbed ciliary localization of membrane-associated proteins ARL13B and INPP5E but normal recruitment of TZ proteins CEP290, RPGRIP1L and NPHP5. The exogenous expression of ciliopathy-associated TMEM67 mutants restored ciliary localization of ARL13B and INPP5E but failed to attenuate aberrant cilium elongation in TMEM67-KO cells. Furthermore, we found that TMEM67 localization is not confined to the TZ but extends into the cilium. Our findings indicate that TMEM67 is required not only for ciliogenesis and cilium length regulation but also for the gating function of the TZ independently of RPGRIP1L/CEP290/NPHP5 recruitment to this region. They further suggest that aberrant cilium elongation underlies the pathogenesis of TMEM67-linked ciliopathies.
    Keywords:  ARL13B; INPP5E; Primary cilia; TMEM67; Transition zone
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.078
  5. Front Neurol. 2022 ;13 1004909
    Clinical and genetic study of a Chinese family affected by both amyotrophic lateral sclerosis and autosomal dominant polycystic kidney disease.
    Shirong Li, Junyu Lin, Chunyu Li, Yongping Chen, Bei Cao, Tianmi Yang, Qianqian Wei, Bi Zhao, Xueping Chen, Huifang Shang.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of the upper and lower motor neurons from the motor cortex, brainstem, and spinal cord. Most ALS cases are sporadic, with 5-10% having a positive family history. Autosomal dominant polycystic kidney disease (ADPKD) is a heritable renal disease that eventually results in end-stage kidney disease. PKD1 is the most prevalent causative gene for ADPKD, accounting for ~85% of cases. Both diseases are currently considered untreatable. In this study, we report a large family that includes 10 patients with ALS phenotype, 3 asymptomatic SOD1-H47R carriers, and 6 with the ADPKD phenotype. Using whole exome sequencing, we found a novel likely pathogenic variant (p.R2787P) in PKD1 among patients with ADPKD, and a pathogenic variant (p.H47R) in SOD1 among patients with ALS. This study highlights the possibility that two different autosomal dominantly inherited diseases can co-exist independently within the same family. Phenotype-genotype correlations among these patients are also described. This research contributes novel phenotype and genotype characteristics of ALS with SOD1 mutations and ADPKD with PKD1 mutations.
    Keywords:  Chinese; PKD1; SOD1; amyotrophic lateral sclerosis; autosomal dominant polycystic kidney disease (ADPKD)
    DOI:  https://doi.org/10.3389/fneur.2022.1004909
  6. Mol Reprod Dev. 2022 Nov 11.
    Structures and functions of cilia during vertebrate embryo development.
    Jeffrey D Amack.
      Cilia are hair-like structures that project from the surface of cells. In vertebrates, most cells have an immotile primary cilium that mediates cell signaling, and some specialized cells assemble one or multiple cilia that are motile and beat synchronously to move fluids in one direction. Gene mutations that alter cilia structure or function cause a broad spectrum of disorders termed ciliopathies that impact virtually every system in the body. A wide range of birth defects associated with ciliopathies underscores critical functions for cilia during embryonic development. In many cases, the mechanisms underlying cilia functions during development and disease remain poorly understood. This review describes different types of cilia in vertebrate embryos and discusses recent research results from diverse model systems that provide novel insights into how cilia form and function during embryo development. The work discussed here not only expands our understanding of in vivo cilia biology, but also opens new questions about cilia and their roles in establishing healthy embryos.
    Keywords:  birth defects; ciliopathies; embryonic development; multiciliated cells; primary cilia
    DOI:  https://doi.org/10.1002/mrd.23650
  7. Pan Afr Med J. 2022 ;42 270
    Autosomal dominant polycystic kidney.
    Rugaved Raghavendra Gudadhe, Gaurav Rajendra Sawarkar.
      
    Keywords:  Polycystic kidney; dialysis; nephrectomy; renal failure
    DOI:  https://doi.org/10.11604/pamj.2022.42.270.36599
  8. Methods Mol Biol. 2023 ;2598 157-176
    Techniques for Visualization and Quantification of Primary Cilia in Chondrocytes.
    Huan Meng, Clare L Thompson, Clarissa R Coveney, Angus K Wann, Martin M Knight.
      Primary cilia regulate and coordinate a variety of cell signaling pathways important in chondrocyte physiology and cartilage development, health, and disease. Despite this, the chondrocyte primary cilium and its associated role in cartilage biology remains poorly understood. Key to elucidating primary cilia structure and function in chondrocytes is the ability to visualize this unique structure. Here we describe materials and methods for immunofluorescence labeling, microscopy, and measurement of chondrocyte primary cilia.
    Keywords:  Chondrocyte; Confocal microscopy; Immunofluorescence; Primary cilia; Quantification; Super resolution
    DOI:  https://doi.org/10.1007/978-1-0716-2839-3_12
  9. Physiol Rep. 2022 Nov;10(21): e15510
    Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.
    Biyang Xu, Oksana Nikolaienko, Vladislav Levchenko, Apurva Swapnil Choubey, Elena Isaeva, Alexander Staruschenko, Oleg Palygin.
      Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4 R allosteric modulator) and 5-BDBD (P2X4 R antagonist) on the development of ARPKD in PCK/CrljCrl-Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP-mediated P2X4 R signaling with ivermectin for 6 weeks in high dose (50 mg/L; water supplementation) decreased the total body weight of PCK rats while the heart and kidney weight remained unaffected. Smaller doses of ivermectin (0.5 or 5 mg/L, 6 weeks) or the inhibition of P2X4 R signaling with 5-BDBD (18 mg/kg/day, food supplement for 8 weeks) showed no effect on electrolyte balance or the basic physiological parameters. Furthermore, cystic index analysis for kidneys and liver revealed no effect of smaller doses of ivermectin (0.5 or 5 mg/L) and 5-BDBD on the cyst development of PCK rats. We observed a slight increase in the cystic liver index on high ivermectin dose, possibly due to the cytotoxicity of the drug. In conclusion, this study revealed that pharmacological modulation of P2X4 R by ivermectin or 5-BDBD does not affect the development of ARPKD in PCK rats, which may provide insights for future studies on investigating the therapeutic potential of adenosine triphosphate (ATP)-P2 signaling in PKD diseases.
    Keywords:  5-BDBD; PCK rats; chronic treatment; ivermectin; kidney; polycystic kidney disease
    DOI:  https://doi.org/10.14814/phy2.15510
  10. J Nephrol. 2022 Nov 07.
    Urinary epidermal growth factor/monocyte chemotactic peptide 1 ratio as non-invasive predictor of Mayo clinic imaging classes in autosomal dominant polycystic kidney disease.
    (Studio PRE. MED. (MEDicina di PREcisione) Prog.n.F/050065/01-02/X32)
       BACKGROUND: Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes.
    METHODS: Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression.
    RESULTS: Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15).
    CONCLUSION: The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease.
    Keywords:  ADPKD; CKD progression urine biomarkers; EGF/MCP1; Risk prediction
    DOI:  https://doi.org/10.1007/s40620-022-01468-w
  11. J Cell Biol. 2023 Jan 02. pii: e202108101. [Epub ahead of print]222(1):
    The β-cell primary cilium is an autonomous Ca2+ compartment for paracrine GABA signaling.
    Gonzalo Manuel Sanchez, Tugce Ceren Incedal, Juan Prada, Paul O'Callaghan, Oleg Dyachok, Santiago Echeverry, Özge Dumral, Phuoc My Nguyen, Beichen Xie, Sebastian Barg, Johan Kreuger, Thomas Dandekar, Olof Idevall-Hagren.
      The primary cilium is an organelle present in most adult mammalian cells that is considered as an antenna for sensing the local microenvironment. Here, we use intact mouse pancreatic islets of Langerhans to investigate signaling properties of the primary cilium in insulin-secreting β-cells. We find that GABAB1 receptors are strongly enriched at the base of the cilium, but are mobilized to more distal locations upon agonist binding. Using cilia-targeted Ca2+ indicators, we find that activation of GABAB1 receptors induces selective Ca2+ influx into primary cilia through a mechanism that requires voltage-dependent Ca2+ channel activation. Islet β-cells utilize cytosolic Ca2+ increases as the main trigger for insulin secretion, yet we find that increases in cytosolic Ca2+ fail to propagate into the cilium, and that this isolation is largely due to enhanced Ca2+ extrusion in the cilium. Our work reveals local GABA action on primary cilia that involves Ca2+ influx and depends on restricted Ca2+ diffusion between the cilium and cytosol.
    DOI:  https://doi.org/10.1083/jcb.202108101
  12. Sci Rep. 2022 Nov 08. 12(1): 19028
    The apical ciliary adhesion complex is established at the basal foot of motile cilia and depends on the microtubule network.
    Maria Chatzifrangkeskou, Paris A Skourides.
      The Ciliary Adhesion (CA) complex forms in close association with the basal bodies of cilia during the early stages of ciliogenesis and is responsible for mediating complex interactions with the actin networks of multiciliated cells (MCCs). However, its precise localization with respect to basal body accessory structures and the interactions that lead to its establishment in MCCs are not well understood. Here, we studied the distribution of the CA proteins using super-resolution imaging and possible interactions with the microtubule network. The results of this study reveal that the apical CA complex forms at the distal end of the basal foot and depends on microtubules. Our data also raise the possibility that CAs may have additional roles in the regulation of the organization of the microtubule network of MCCs.
    DOI:  https://doi.org/10.1038/s41598-022-22871-0
  13. Osteoarthritis Cartilage. 2022 Nov 08. pii: S1063-4584(22)00913-X. [Epub ahead of print]
    YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression.
    Huan Meng, Su Fu, Marta B Ferreira, Yu Hou, Oliver M Pearce, Nuria Gavara, Martin M Knight.
       OBJECTIVE: To clarify the role of YAP in modulating cartilage inflammation and degradation and the involvement of primary cilia and associated intraflagellar transport (IFT).
    METHODS: Isolated primary chondrocytes were cultured on substrates of different stiffness (6-1000kPa) or treated with YAP agonist lysophosphatidic acid (LPA) or YAP antagonist verteporfin (VP), or genetically modified by YAP siRNA, all ±IL1β. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were measured to monitor IL1β response. YAP activity was quantified by YAP nuclear/cytoplasmic ratio and percentage of YAP-positive cells. Mechanical properties of cartilage explants were tested to confirm cartilage degradation. The involvement of primary cilia and IFT was analysed using IFT88 siRNA and ORPK cells with hypomorphic mutation of IFT88.
    RESULTS: Treatment with LPA, or increasing PDMS substrate stiffness, activated YAP nuclear expression and inhibited IL1β-induced release of NO and PGE2, in isolated chondrocytes. Treatment with LPA also inhibited IL1β-mediated inflammatory signalling in cartilage explants and prevented matrix degradation and the loss of cartilage biomechanics. YAP activation reduced expression of primary cilia, knockdown of YAP in the absence of functional cilia/IFT failed to induce an inflammatory response.
    CONCLUSIONS: We demonstrate that both pharmaceutical and mechanical activation of YAP blocks pro-inflammatory signalling induced by IL1β and prevents cartilage breakdown and the loss of biomechanical functionality. This is associated with reduced expression of primary cilia revealing a potential anti-inflammatory mechanism with novel therapeutic targets for treatment of OA.
    Keywords:  Extracellular matrix stiffness; Yes-associated protein (YAP); inflammatory response; matrix degradation; primary cilia
    DOI:  https://doi.org/10.1016/j.joca.2022.11.001
  14. Cell Regen. 2022 Nov 09. 11(1): 41
    Correction: Cilia regeneration requires an RNA splicing factor from the ciliary base.
    Kaiming Xu, Guangshuo Ou.
      
    DOI:  https://doi.org/10.1186/s13619-022-00147-2
  15. EMBO J. 2022 Nov 10. e112440
    Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B.
    Narcis A Petriman, Marta Loureiro-López, Michael Taschner, Nevin K Zacharia, Magdalena M Georgieva, Niels Boegholm, Jiaolong Wang, André Mourão, Robert B Russell, Jens S Andersen, Esben Lorentzen.
      Cilia are ubiquitous eukaryotic organelles impotant for cellular motility, signaling, and sensory reception. Cilium formation requires intraflagellar transport of structural and signaling components and involves 22 different proteins organized into intraflagellar transport (IFT) complexes IFT-A and IFT-B that are transported by molecular motors. The IFT-B complex constitutes the backbone of polymeric IFT trains carrying cargo between the cilium and the cell body. Currently, high-resolution structures are only available for smaller IFT-B subcomplexes leaving > 50% structurally uncharacterized. Here, we used Alphafold to structurally model the 15-subunit IFT-B complex. The model was validated using cross-linking/mass-spectrometry data on reconstituted IFT-B complexes, X-ray scattering in solution, diffraction from crystals as well as site-directed mutagenesis and protein-binding assays. The IFT-B structure reveals an elongated and highly flexible complex consistent with cryo-electron tomographic reconstructions of IFT trains. The IFT-B complex organizes into IFT-B1 and IFT-B2 parts with binding sites for ciliary cargo and the inactive IFT dynein motor, respectively. Interestingly, our results are consistent with two different binding sites for IFT81/74 on IFT88/70/52/46 suggesting the possibility of different structural architectures for the IFT-B1 complex. Our data present a structural framework to understand IFT-B complex assembly, function, and ciliopathy variants.
    Keywords:  AlphaFold; Cilium; IFT-B structure; Intraflagellar transport; Structural modeling
    DOI:  https://doi.org/10.15252/embj.2022112440
  16. Bioengineering (Basel). 2022 Oct 25. pii: 613. [Epub ahead of print]9(11):
    Effect of Rho-Associated Kinase Inhibitor on Growth Behaviors of Human Induced Pluripotent Stem Cells in Suspension Culture.
    Takaki Matsumoto, Mee-Hae Kim, Masahiro Kino-Oka.
      Rho-associated protein kinase (ROCK) inhibitors are used for the survival of single-dissociated human induced pluripotent stem cells (hiPSCs); however, their effects on the growth behaviors of hiPSCs in suspension culture are unexplored. Therefore, we investigated the effect of ROCK inhibitor on growth behaviors of two hiPSC lines (Tic and 1383D2) with different formation of aggregate that attached between single cells in suspension culture. The apparent specific growth rate by long-term exposure to Y-27632, a ROCK inhibitor, was maintained throughout the culture. Long-term exposure to ROCK inhibitor led to an increase in cell division throughout the culture in both lines. Immunofluorescence staining confirmed that hiPSCs forming spherical aggregates showed localization of collagen type I on its periphery. In addition, phosphorylated myosin (pMLC) was localized at the periphery in culture under short-term exposure to ROCK inhibitor, whereas pMLC was not detected at whole the aggregate in culture under long-term exposure. Scanning electron microscopy indicated that long-term exposure to ROCK inhibitor blocked the structural alteration on the surface of cell aggregates. These results indicate that pMLC inhibition by long-term ROCK inhibition leads to enhanced growth abilities of hiPSCs in suspension culture by maintaining the structures of extracellular matrices.
    Keywords:  Rho–associated kinase inhibitor; aggregate formation; collagen type I; growth behavior; human induced pluripotent stem cell; suspension culture
    DOI:  https://doi.org/10.3390/bioengineering9110613
  17. Am J Pathol. 2022 Nov 03. pii: S0002-9440(22)00356-X. [Epub ahead of print]
    Identification of the electrogenic 2Cl-/H+ exchanger, ClC5, as a chloride secreting transporter candidate in kidney cyst epithelium in tuberous sclerosis.
    Sharon Barone, Marybeth Brooks, Kamyar Zahedi, L Shannon Holliday, John Bissler, Jane J Yu, Manoocher Soleimani.
      Kidney cyst expansion in Tuberous Sclerosis Complex (TSC) or Polycystic Kidney Disease (PKD) requires active secretion of chloride into the cyst lumen. In PKD, Cl- secretion is primarily mediated via CFTR in principal cells. Kidney cystogenesis in TSC is predominantly comprised of A-intercalated cells, which do not exhibit noticeable expression of CFTR. The identity of the Cl- secreting molecule(s) in TSC cyst epithelia remains speculative. Based on RNA seq analysis studies, we examined the expression of FOXi1, the chief regulator of acid base transporters in intercalated cells, along with localization of ClC-5, in kidneys of various models of TSC. Our results in Tsc2+/- mice demonstrate that the expansion of kidney cysts corresponds to the induction of Foxi1 and correlates with the strong appearance of ClC-5 and H+-ATPase on the apical membrane of cyst epithelia. In various mouse models of TSC, Foxi1 is robustly induced in the kidney, and ClC-5 appears along with H+-ATPase on the apical membrane of cyst epithelia. Expression of ClC-5 was also detected on the apical membrane of cyst epithelia in humans with TSC but was absent in humans with ADPKD or in a mouse model of PKD. These results indicate that ClC-5 is expressed on the apical membrane of cyst epithelia and is a likely candidate mediating Cl- secretion into the kidney cyst lumen in TSC.
    DOI:  https://doi.org/10.1016/j.ajpath.2022.10.007
  18. Am J Kidney Dis. 2022 Nov 01. pii: S0272-6386(22)00994-5. [Epub ahead of print]
    Association of the Urine-to-Plasma Urea Ratio With CKD Progression.
    Jing Liu, Lise Bankir, Ashish Verma, Sushrut S Waikar, Ragnar Palsson.
       RATIONALE & OBJECTIVES: The urine-to-plasma ratio of urea ([U/P]urea) is correlated with urine concentrating capacity and associated with progression of autosomal dominant polycystic kidney disease. As a proposed biomarker of tubular function, we hypothesized that [U/P]urea would also be associated with progression of more common forms of chronic kidney disease (CKD).
    STUDY DESIGN: Observational cohort study.
    SETTING & PARTICIPANTS: 3,723 adults in the USA with estimated glomerular filtration rate (eGFR) of 20-70 mL/min per 1.73m2, enrolled in the Chronic Renal Insufficiency Cohort Study.
    EXPOSURE: [U/P]urea, calculated from 24-hour urine collections and plasma samples at baseline.
    OUTCOMES: Associations of [U/P]urea with eGFR slope, incident end-stage kidney disease (ESKD), and CKD progression, defined as 50% decline in eGFR or incident ESKD.
    ANALYTICAL APPROACH: Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes.
    RESULTS: Median (interquartile range) [U/P]urea was 14.8 (IQR, 9.5-22.2). Compared to participants in the highest [U/P]urea quintile, those in the lowest quintile had a greater eGFR decline by 1.06 ml/min per 1.73m2 per year (P<0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up. Each 1 standard deviation decrease in natural log-transformed [U/P]urea was independently associated with CKD progression (HR 1.22, 95% CI 1.12-1.33) and incident ESKD (HR 1.22, 95% CI 1.10-1.33). Associations differed by baseline eGFR (p-interaction=0.009). Among those with an eGFR ≥30 ml/min per 1.73m2, each 1 standard deviation decrease in log-[U/P]urea was independently associated with CKD progression (HR 1.30, 95% CI 1.18-1.45), but this was not significant among those with eGFR <30 ml/min per 1.73m2 (HR 1.00, 95% CI 0.84-1.20).
    LIMITATIONS: Possibility of residual confounding. Single baseline 24-hour urine collection for [U/P]urea.
    CONCLUSIONS: In a large and diverse cohort of patients with common forms of CKD, [U/P]urea was independently associated with disease progression and incident kidney failure. Associations were not significant among those with advanced CKD at baseline.
    DOI:  https://doi.org/10.1053/j.ajkd.2022.09.010
  19. Biosci Rep. 2022 Nov 11. pii: BSR-2015-0032_EOC. [Epub ahead of print]42(11):
    Expression of Concern: FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity.
      
    Keywords:  FSD-C10; Fasudil; Rho kinase; Rho kinase inhibitor
    DOI:  https://doi.org/10.1042/BSR-2015-0032_EOC
  20. Biol Pharm Bull. 2022 Nov 10.
    Transforming growth factor-β1 and bone morphogenetic protein-2 inhibit differentiation into mature ependymal multiciliated cells.
    Takuya Hirao, Beak Gyu Kim, Hinako Habuchi, Kotoku Kawaguchi, Takashi Nakahari, Yoshinori Marunaka, Shinji Asano.
      Ependymal cilia play pivotal roles in cerebrospinal fluid flow. In the primary culture system, undifferentiated glial cells differentiate well into ependymal multiciliated cells (MCCs) in the absence of fetal bovine serum (FBS). However, the substances included in FBS which inhibit this differentiation process have not been clarified yet. Here, we constructed the polarized primary culture system of ependymal cells using a permeable filter in which they retained ciliary movement. We found that transforming growth factor-β1 (TGF-β1) as well as Bone morphogenetic protein (BMP)-2 inhibited the differentiation with ciliary movement. The inhibition on the differentiation by FBS was recovered by the TGF-β1 and BMP-2 inhibitors in combination.
    Keywords:  bone morphogenetic protein−2; cilium; ependymal cells; primary culture; transforming growth factor−β1
    DOI:  https://doi.org/10.1248/bpb.b22-00733
  21. Neurobiol Dis. 2022 Oct 29. pii: S0969-9961(22)00305-9. [Epub ahead of print]175 105913
    Rethinking the cilia hypothesis of hydrocephalus.
    Phan Q Duy, Ana B W Greenberg, William E Butler, Kristopher T Kahle.
      Dysfunction of motile cilia in ependymal cells has been proposed to be a pathogenic cause of cerebrospinal fluid (CSF) overaccumulation leading to ventricular expansion in hydrocephalus, primarily based on observations of enlarged ventricles in mouse models of primary ciliary dyskinesia. Here, we review human and animal evidence that warrants a rethinking of the cilia hypothesis in hydrocephalus. First, we discuss neuroembryology and physiology data that do not support a role for ependymal cilia as the primary propeller of CSF movement across the ventricles in the human brain, particularly during in utero development prior to the functional maturation of ependymal cilia. Second, we highlight that in contrast to mouse models, motile ciliopathies infrequently cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function impact not only ependymal cilia but also motile cilia found in other organ systems outside of the brain, causing a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that do not typically accompany most cases of human hydrocephalus. Finally, we postulate that certain cases of hydrocephalus associated with ciliary gene mutations may arise not necessarily just from loss of cilia-generated CSF flow but also from altered neurodevelopment, given the potential functions of ciliary genes in signaling and neural stem cell fate beyond generating fluid flow. Further investigations are needed to clarify the link between motile cilia, CSF physiology, and brain development, the understanding of which has implications for the care of patients with hydrocephalus and other related neurodevelopmental disorders.
    Keywords:  Cerebrospinal fluid; Cilia; Ciliopathies; Ependymal cells; Hydrocephalus; Primary ciliary dyskinesia; Ventricles
    DOI:  https://doi.org/10.1016/j.nbd.2022.105913
  22. Neuron. 2022 Oct 29. pii: S0896-6273(22)00947-3. [Epub ahead of print]
    CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signaling to promote expansion of cortical progenitors.
    Roxane Van Heurck, Jérôme Bonnefont, Marta Wojno, Ikuo K Suzuki, Fausto D Velez-Bravo, Emir Erkol, Dan Truc Nguyen, Adèle Herpoel, Angéline Bilheu, Sofie Beckers, Catherine Ledent, Pierre Vanderhaeghen.
      The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors. CROCCP2 decreases ciliary dynamics by inhibition of the IFT20 ciliary trafficking protein, which then impacts neurogenesis through increased mTOR signaling. Loss of function of CROCCP2 in human cortical cells and organoids leads to increased ciliogenesis, decreased mTOR signaling, and impaired basal progenitor amplification. These data identify CROCCP2 as a human-specific modifier of cortical neurogenesis that acts through modulation of ciliary dynamics and mTOR signaling.
    Keywords:  CROCC; CROCCP2; cerebral cortex; cilia; evolution; human brain development; mTOR; neurogenesis; rootlet; rootletin
    DOI:  https://doi.org/10.1016/j.neuron.2022.10.018
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