bims-bicyki 2022-07-17 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–07–17
twenty-two papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis.
Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease.
Nephrotic syndrome in autosomal dominant polycystic kidney disease in children versus adults: Answers.
Nephrotic syndrome in autosomal dominant polycystic kidney disease in children versus adults: Questions.
The Enigma of Clinical Heterogeneity Among Autosomal Recessive Polycystic Kidney Disease Siblings: PKHD1 Genotype Versus Other Genomic or Environmental Modifier.
Bleeding risk in patients with autosomal dominant polycystic kidney disease treated with acetylsalicylic acid: implications for prevention of preeclampsia.
The Need for Routine Native Nephrectomy in the Workup for Kidney Transplantation in Autosomal Dominant Polycystic Kidney Disease Patients.
[Tolvaptan in ADPKD patients at the University of Padova Nephrology Unit: impact on quality of life, efficacy and safety].
Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease.
Subgroup-specific roles of primary cilia in medulloblastoma.
Cilia Action in Islets: Lessons From Mouse Models.
Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme.
The intraflagellar transport protein IFT52 associated with short-rib thoracic dysplasia is essential for ciliary function in osteogenic differentiation in vitro and for sensory perception in Drosophila.
Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding.
Reply to Yang Zhao, Wenda Wang, and Yushi Zhang's Letter to the Editor re: Sounak Gupta, Christine M. Lohse, Ross Rowsey, et al. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex-associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome. Eur Urol 2022;81:229-33.
Effect of ultra-mini percutaneous nephrolithotomy and ShuoTong ureteroscopy on the stress response, inflammatory indices, and urokinase level in patients with polycystic kidney disease complicated with renal calculus.
Enhancement of airway ciliary beating mediated via voltage-gated Ca2+ channels/α7-nicotinic receptors in mice.
Primary ciliary dyskinesia with CCDC39 variants displaying specific ciliary ultrastructure and movement concordant with the genotype: A case report.
dmrt2 and myf5 Link Early Somitogenesis to Left-Right Axis Determination in Xenopus laevis.
Kidney Histology Findings in a Patient with Autosomal Dominant Tubulointerstitial Kidney Disease Subtype Hepatocyte Nuclear Factor 1β.
Psychological status of mothers of children with cystic fibrosis and primary ciliary dyskinesia.
NEK7: a new target for the treatment of multiple tumors and chronic inflammatory diseases.

Front Mol Biosci. 2022 ;9 936070

Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis.

Rebecca V Walker, Anthony Maranto, Vivek Reddy Palicharla, Sun-Hee Hwang, Saikat Mukhopadhyay, Feng Qian.

  Primary cilia play counterregulatory roles in cystogenesis-they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.

Keywords:  cilia-dependent cyst activation; cilia-localized cyst inhibition; cystogenesis; intraflagellar transport; polycystic kidney disease; polycystin 1 and 2; primary cilia; tubby-like protein 3

DOI:  https://doi.org/10.3389/fmolb.2022.936070
J Am Soc Nephrol. 2022 Jul 14. pii: ASN.2022010053. [Epub ahead of print]

Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease.

Biswajit Padhy, Jian Xie, Runping Wang, Fang Lin, Chou-Long Huang.

   BACKGROUND: Mutations of PKD2, which encodes polycystin-2, cause autosomal dominant polycystic kidney disease (ADPKD). The prevailing view is that defects in polycystin-2-mediated calcium ion influx in the primary cilia play a central role in the pathogenesis of cyst growth. However, polycystin-2 is predominantly expressed in the endoplasmic reticulum (ER) and more permeable to potassium ions than to calcium ions.
METHODS: The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium ion release. Using TRIC-B as a tool, we examined the function of ER-localized polycystin-2 and its role in ADPKD pathogenesis in cultured cells, zebrafish, and mouse models.
RESULTS: Agonist-induced ER calcium ion release was defective in cells lacking polycystin-2, and reversed by exogenous expression of TRIC-B. Vice versa, exogenous polycystin-2 reversed an ER calcium-release defect in cells lacking TRIC-B. In a zebrafish model, expression of wild-type but not nonfunctional TRIC-B suppressed polycystin-2-deficient phenotypes. Similarly, these phenotypes were suppressed by targeting the ROMK potassium channel (normally expressed on the cell surface) to the ER. In cultured cells and polycystin-2-deficient zebrafish phenotypes, polycystin-2 remained capable of reversing the ER calcium release defect even when it was not present in the cilia. Transgenic expression of Tric-b ameliorated cystogenesis in the kidneys of conditional Pkd2-inactivated mice, whereas Tric-b deletion enhanced cystogenesis in Pkd2-heterozygous kidneys.
CONCLUSIONS: Polycystin-2 in the ER appears to be critical for anticystogenesis and likely functions as a potassium ion channel to facilitate potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium release. The results advance the understanding of ADPKD pathogenesis and provides proof of principle for pharmacotherapy by TRIC-B activators.

Keywords:  ADPKD; endoplasmic reticulum; ion channel; polycystin

DOI:  https://doi.org/10.1681/ASN.2022010053
Pediatr Nephrol. 2022 Jul 15.

Nephrotic syndrome in autosomal dominant polycystic kidney disease in children versus adults: Answers.

Mohammad Ilyas, Rudolph Well, Aleena Blake, Asad Tolaymat.



Keywords:  Autosomal dominant polycystic kidney disease; Glomerulopathy; Kidney biopsy, Adults versus children; Nephrotic syndrome

DOI:  https://doi.org/10.1007/s00467-022-05617-y
Pediatr Nephrol. 2022 Jul 15.

Nephrotic syndrome in autosomal dominant polycystic kidney disease in children versus adults: Questions.

Mohammad Ilyas, Rudolph Well, Aleena Blake, Asad Tolaymat.



Keywords:  Adults versus children; Autosomal dominant polycystic kidney disease; Glomerulopathy; Kidney biopsy; Nephrotic syndrome

DOI:  https://doi.org/10.1007/s00467-022-05597-z
Kidney Int Rep. 2022 Jul;7(7): 1453-1455

The Enigma of Clinical Heterogeneity Among Autosomal Recessive Polycystic Kidney Disease Siblings: PKHD1 Genotype Versus Other Genomic or Environmental Modifier.

Priti Meena, Katharina Hopp.

DOI: https://doi.org/10.1016/j.ekir.2022.04.092
J Nephrol. 2022 Jul 13.

Bleeding risk in patients with autosomal dominant polycystic kidney disease treated with acetylsalicylic acid: implications for prevention of preeclampsia.

DIPAK consortium



Keywords:  ADPKD; Acetylsalicylic acid; Cyst bleeding; Hematuria; Preeclampsia; Pregnancy

DOI:  https://doi.org/10.1007/s40620-022-01393-y
Urol Int. 2022 Jul 08. 1-9

The Need for Routine Native Nephrectomy in the Workup for Kidney Transplantation in Autosomal Dominant Polycystic Kidney Disease Patients.

Niek F Casteleijn, Paul Geertsema, Iris W Koorevaar, Friso D J Inkelaar, Marnix R Jansen, Steven J Lohuis, Esther Meijer, Robert A Pol, Jan-Stephan Sanders, Peter E van de Streek, Anna M Leliveld, Ron T Gansevoort.

   INTRODUCTION: There is no consensus if nor when a native nephrectomy should be performed in the workup for kidney transplantation in ADPKD patients. In our PKD Expertise Center, a restrictive approach is pursued in which nephrectomy is performed only in patients with severe complaints, i.e., in case of serious volume-related complaints, lack of space for the allograft, recurrent cyst infections, persistent cyst bleedings, or chronic refractory pain. We analyzed in a retrospective cohort study whether this approach is justified.
METHODS: All ADPKD patients who received kidney transplantation between January 2000 and January 2019 were reviewed. Patients were subdivided into three groups: no nephrectomy (no-Nx), nephrectomy performed before (pre-Tx), or after kidney transplantation (post-Tx). Simultaneous nephrectomy together with transplantation were not performed in our center.
RESULTS: 391 patients (54 ± 9 years, 55% male) were included. The majority of patients did not undergo a nephrectomy (n = 257, 65.7%). A nephrectomy was performed pre-Tx in 114 patients (29.2%). After Tx, nephrectomy was performed in only 30 patients (7.7%, median 4.4 years post-Tx). Surgery-related complication rates did not differ between both groups (38.3% pre-Tx vs. 27.0% post-Tx, p = 0.2), nor were there any differences in 10-year patient survival (74.4% pre-Tx vs. 80.7% post-Tx vs. 67.6% no-Nx, p = 0.4), as well as in 10-year death-censored graft survival (84.4% pre-Tx vs. 85.5% post-Tx vs. 90.0% no-Nx, p = 0.9).
CONCLUSIONS: This study indicates that with a restrictive nephrectomy policy in the workup for kidney transplantation, only a part of ADPKD patients need a native nephrectomy.

Keywords:  Autosomal dominant polycystic kidney disease; Nephrectomy; Polycystic kidney disease; Transplantation

DOI:  https://doi.org/10.1159/000525575
G Ital Nefrol. 2022 Jun 20. pii: 2022-vol3. [Epub ahead of print]39(3):

[Tolvaptan in ADPKD patients at the University of Padova Nephrology Unit: impact on quality of life, efficacy and safety].

Irene Cirella, Valentina di Vico, Matteo Rigato, Beatrice Bugnotto, Paola Baldini Anastasio, Daniela Campo, Gianni Carraro, Lorenzo A Calò.

Autosomal dominant polycystic kidney disease (ADPKD) is responsible of the 10% of the dialysis patients. Tolvaptan is a consolidate option for treatment of ADPKD patients; it slows renal deterioration rate and cysts' growth, although its acquaretic effects often impact on quality of life (QoL) and treatment adherence. Few studies have documented the tolvaptan long term efficacy and safeness profiles and, mostly, the impact of treatment with tolvaptan on patients' QoL. Our study aimed to investigate in 13 ADPKD patients of our cohort the differences in terms of QoL before and after the start of treatment via a questionnaire based on SF-36 and PSQI tests, integrated with other original questions. In addition we have also examined the tolvaptan long term efficacy and safeness profiles. The results of our study show that tolvaptan does not significantly reduce patients QoL notwithstanding its expected acquaretic effects, the only reported side effects. Finally, the average annual renal deterioration rate was lower in patients treated with tolvaptan than in the others. Relevant limits of our study are the small number of selected patients and the relative short study duration. However, on one hand, the results of our study provide further information to the few data available in literature; on the other hand, they may serve as a useful working hypothesis for further studies with a larger number of patients enrolled and an extended study duration. They would demonstrate the absence of significant impact of tolvaptan on patients' QoL.

Keywords: ADPKD; QoL; tolvaptan
Kidney Int Rep. 2022 Jul;7(7): 1643-1652

Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease.

Ramona Ajiri, Kathrin Burgmaier, Nurver Akinci, Ilse Broekaert, Anja Büscher, Ismail Dursun, Ali Duzova, Loai Akram Eid, Marc Fila, Michaela Gessner, Ibrahim Gokce, Laura Massella, Antonio Mastrangelo, Monika Miklaszewska, Larisa Prikhodina, Bruno Ranchin, Nadejda Ranguelov, Rina Rus, Lale Sever, Julia Thumfart, Lutz Thorsten Weber, Elke Wühl, Alev Yilmaz, Jörg Dötsch, Franz Schaefer, Max Christoph Liebau.

   Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood.
Methods: We present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings.
Results: We identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1-6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2-6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age.
Conclusion: In patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype.

Keywords:  ARPKD; Ciliopathies; DZIP1L; Fibrocystin; PKD; PKHD1

DOI:  https://doi.org/10.1016/j.ekir.2022.04.095
Genes Dev. 2022 Jun 01. 36(11-12): 650-651

Subgroup-specific roles of primary cilia in medulloblastoma.

Silvia Marino.

  Here I discuss the study in this issue of Genes & Development by Youn et al. (pp. 737-751), which describes defined and diverse roles of primary cilia in molecularly distinct medulloblastoma subgroups, highlighting once again the importance of designing subgroup-specific therapeutic approaches for this tumor.

Keywords:  WNT; cell cycle; cilia; medulloblastoma; translation

DOI:  https://doi.org/10.1101/gad.349856.122
Front Endocrinol (Lausanne). 2022 ;13 922983

Cilia Action in Islets: Lessons From Mouse Models.

Jung Hoon Cho, Jing W Hughes.

  Primary cilia as a signaling organelle have garnered recent attention as a regulator of pancreatic islet function. These rod-like sensors exist on all major islet endocrine cell types and transduce a variety of external cues, while dysregulation of cilia function contributes to the development of diabetes. The complex role of islet primary cilia has been examined using genetic deletion targeting various components of cilia. In this review, we summarize experimental models for the study of islet cilia and current understanding of mechanisms of cilia regulation of islet hormone secretion. Consensus from these studies shows that pancreatic cilia perturbation can cause both endocrine and exocrine defects that are relevant to human disease. We discuss future research directions that would further elucidate cilia action in distinct groups of islet cells, including paracrine and juxtacrine regulation, GPCR signaling, and endocrine-exocrine crosstalk.

Keywords:  hormone regulation; insulin secretion; pancreatic islets; primary cilia; β-cells

DOI:  https://doi.org/10.3389/fendo.2022.922983
Front Endocrinol (Lausanne). 2022 ;13 922825

Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme.

Marta Pablos, Elena Casanueva-Álvarez, Carlos M González-Casimiro, Beatriz Merino, Germán Perdomo, Irene Cózar-Castellano.

  The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.

Keywords:  insulin; insulin signaling; insulin-degrading enzyme; pancreas; primary cilium; proliferation; α-cell; β-cell

DOI:  https://doi.org/10.3389/fendo.2022.922825
Exp Cell Res. 2022 Jul 12. pii: S0014-4827(22)00266-X. [Epub ahead of print] 113273

The intraflagellar transport protein IFT52 associated with short-rib thoracic dysplasia is essential for ciliary function in osteogenic differentiation in vitro and for sensory perception in Drosophila.

Vishal Singh Guleria, Rahul Parit, Neha Quadri, Ranajit Das, Priyanka Upadhyai.

  Primary cilia are non-motile sensory cell-organelle that are essential for organismal development, differentiation, and postnatal homeostasis. Their biogenesis and function are mediated by the intraflagellar transport (IFT) system. Pathogenic variants in IFT52, a central component of the IFT-B complex is associated with short-rib thoracic dysplasia with or without polydactyly 16 (SRTD16), with major skeletal manifestations, in addition to other features. Here we sought to examine the role of IFT52 in osteoblast differentiation. Using lentiviral shRNA interference Ift52 was depleted in C3H10T1/2 mouse mesenchymal stem cells. This led to the disruption of the IFT-B anterograde trafficking machinery that impaired primary ciliogenesis and blocked osteogenic differentiation. In Ift52 silenced cells, Hedgehog (Hh) pathway upregulation during osteogenesis was attenuated and despite Smoothened Agonist (SAG) based Hh activation, osteogenic differentiation was incompletely restored. Further we investigated IFT52 activity in Drosophila, wherein the only ciliated somatic cells are the bipolar sensory neurons of the peripheral nervous system. Knockdown of IFT52 in Drosophila neuronal tissues reduced lifespan with the loss of embryonic chordotonal cilia, and produced severe locomotion, auditory and proprioceptive defects in larva and adults. Together these findings improve our knowledge of the role of IFT52 in various physiological contexts and its associated human disorder.

Keywords:  Ciliopathy; Drosophila as disease model; IFT52; Osteogenic differentiation; Primary cilia; Short-rib thoracic dysplasia

DOI:  https://doi.org/10.1016/j.yexcr.2022.113273
Nat Commun. 2022 Jul 09. 13(1): 3997

Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding.

Liang Wang, Xin Wen, Zhengmao Wang, Zaisheng Lin, Chunhong Li, Huilin Zhou, Huimin Yu, Yuhan Li, Yifei Cheng, Yuling Chen, Geer Lou, Junmin Pan, Muqing Cao.

The transition zone (TZ) of the cilium/flagellum serves as a diffusion barrier that controls the entry/exit of ciliary proteins. Mutations of the TZ proteins disrupt barrier function and lead to multiple human diseases. However, the systematic regulation of ciliary composition and signaling-related processes by different TZ proteins is not completely understood. Here, we reveal that loss of TCTN1 in Chlamydomonas reinhardtii disrupts the assembly of wedge-shaped structures in the TZ. Proteomic analysis of cilia from WT and three TZ mutants, tctn1, cep290, and nphp4, shows a unique role of each TZ subunit in the regulation of ciliary composition, explaining the phenotypic diversity of different TZ mutants. Interestingly, we find that defects in the TZ impair the formation and biological activity of ciliary ectosomes. Collectively, our findings provide systematic insights into the regulation of ciliary composition by TZ proteins and reveal a link between the TZ and ciliary ectosomes.

DOI: https://doi.org/10.1038/s41467-022-31751-0
Eur Urol. 2022 Jul 06. pii: S0302-2838(22)02473-3. [Epub ahead of print]

Reply to Yang Zhao, Wenda Wang, and Yushi Zhang's Letter to the Editor re: Sounak Gupta, Christine M. Lohse, Ross Rowsey, et al. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex-associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome. Eur Urol 2022;81:229-33.

Sounak Gupta, Christine M Lohse, Rafael E Jimenez, John C Cheville.

DOI: https://doi.org/10.1016/j.eururo.2022.06.022
Cell Mol Biol (Noisy-le-grand). 2022 Feb 04. 67(5): 309-316

Effect of ultra-mini percutaneous nephrolithotomy and ShuoTong ureteroscopy on the stress response, inflammatory indices, and urokinase level in patients with polycystic kidney disease complicated with renal calculus.

Du Qiao, Luo Cheng, Tian Xiaomei, Shi Baolei, Li Yingyi, Zhang Hui, Bian Shaohua, Liu Wei, Dai Y U, Deng Fangqiong, Liu Jie, Liu Shuangning.

This study aimed to explore the effects of ultra-mini percutaneous nephrolithotomy (UMP) combined with ShuoTong ureteroscopy on the stress response, inflammation indicators and urokinase levels in patients with polycystic kidney disease and kidney stones. In this study, 42 patients with polycystic kidney disease and kidney stones diagnosed and treated in our hospital from February 2018 to February 2021 were selected as the research objects. They were randomly divided into the control group and the study group, with 21 cases in each group, and the control group adopted Ultra-mini percutaneous nephrolithotomy treatment; the study group was combined with ShuoTong ureteroscopy on the basis of the control group, and compared and analyzed the stress response, inflammation indexes, urokinase level, renal function, complications and stone clearance rate of the two groups of patients. After treatment, the average operation time, channel establishment time, hemoglobin decline, number of puncture channels, and hospital stay in the study group were significantly shorter than those in the control group (P<0.05); after treatment, the reduction in CRP and PCT in the study group was significantly higher than that in the control group The increase of Ang I and Ang II in the control group was significantly lower than that in the control group (P<0.05); the improvement of PGE2, NO, and LPO levels in the study group was significantly higher than that in the control group after treatment (P<0.05); the study group TH, Cys- The levels of C and β2-MG were significantly lower than those of the control group; the UK levels of the study group were significantly lower than those of the control group (P<0.05); the complication rate of 14.29% in the study group after treatment was significantly lower than that of the control group 33.33%; the study group The stone clearance rate of 95.24% was significantly higher than that of the control group 80.95% (P<0.05). In general, UMP combined with ShuoTong ureteroscopy is used to treat polycystic kidney with kidney stones, accurately determine the tip position of the needle sheath, ensure that the needle sheath enters the collection system to adjust its position, reduce patient stress and inflammation, improve safety and feasibility, and is worthy of clinical practice Promote applications.

DOI: https://doi.org/10.14715/cmb/2021.67.5.42
Pflugers Arch. 2022 Jul 11.

Enhancement of airway ciliary beating mediated via voltage-gated Ca2+ channels/α7-nicotinic receptors in mice.

Daichi Saitoh, Kotoku Kawaguchi, Shinji Asano, Toshio Inui, Yoshinori Marunaka, Takashi Nakahari.

  Acetylcholine (ACh), which activates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs), enhances airway ciliary beating by increasing the intracellular Ca2+ concentration ([Ca2+]i). The mechanisms enhancing airway ciliary beating by nAChRs have remained largely unknown, although those by mAChRs are well understood. In this study, we focused on the effects of α7-nAChRs and voltage-gated Ca2+ channels (CaVs) on the airway ciliary beating. The activities of ciliary beating were assessed by frequency (CBF, ciliary beat frequency) and amplitude (CBD, ciliary bend distance) measured by high-speed video microscopy. ACh enhanced CBF and CBD by 25% mediated by an [Ca2+]i increase stimulated by mAChRs and α7-nAChRs (a subunit of nAChR) in airway ciliary cells of mice. Experiments using PNU282987 (an agonist of α7-nAChR) and MLA (an inhibitor of α7-nAChR) revealed that CBF and CBD enhanced by α7-nAChR are approximately 50% of those enhanced by ACh. CBF, CBD, and [Ca2+]i enhanced by α7-nAChRs were inhibited by nifedipine, suggesting activation of CaVs by α7-nAChRs. Experiments using a high K+ solution with/without nifedipine (155.5 mM K+) showed that the activation of CaVs enhances CBF and CBD via an [Ca2+]i increase. Immunofluorescence and immunoblotting studies demonstrated that Cav1.2 and α7-nAChR are expressed in airway cilia. Moreover, IL-13 stimulated MLA-sensitive increases in CBF and CBD in airway ciliary cells, suggesting an autocrine regulation of ciliary beating by CaV1.2/α7-nAChR/ACh. In conclusion, a novel Ca2+ signalling pathway in airway cilia, CaV1.2/α7-nAChR, enhances CBF and CBD and activates mucociliary clearance maintaining healthy airways.

Keywords:  Airway; Ciliary beating; Intracellular Ca2+ concentration; VDCC; α7 nicotinic acetylcholine receptor

DOI:  https://doi.org/10.1007/s00424-022-02724-5
Respir Investig. 2022 Jul 08. pii: S2212-5345(22)00060-0. [Epub ahead of print]

Primary ciliary dyskinesia with CCDC39 variants displaying specific ciliary ultrastructure and movement concordant with the genotype: A case report.

Miki Abo, Kazuhiko Takeuchi, Makoto Ikejiri, Takayoshi Ueno, Tomoaki Yoneda, Johsuke Hara, Noriyuki Ohkura, Satoshi Watanabe, Kazuo Kasahara, Seiji Yano.

  Primary ciliary dyskinesia (PCD) is a genetic disease with chronic airway infection and inflammation caused by ciliary ultrastructural defects and impairment in ciliary function. We present an adult case of PCD with compound heterozygous nonsense variants in CCDC39. The ciliary ultrastructure findings using electron microscopy and ciliary movement using high-speed video analysis matched the genotype. This is the first case report of PCD with CCDC39 variants in Japan demonstrating specific ciliary ultrastructure and movement related to the genotype.

Keywords:  CCDC39 variant; High-speed video analysis; Primary ciliary dyskinesia; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.resinv.2022.05.005
Front Cell Dev Biol. 2022 ;10 858272

dmrt2 and myf5 Link Early Somitogenesis to Left-Right Axis Determination in Xenopus laevis.

Melanie Tingler, Amelie Brugger, Kerstin Feistel, Axel Schweickert.

  The vertebrate left-right axis is specified during neurulation by events occurring in a transient ciliated epithelium termed left-right organizer (LRO), which is made up of two distinct cell types. In the axial midline, central LRO (cLRO) cells project motile monocilia and generate a leftward fluid flow, which represents the mechanism of symmetry breakage. This directional fluid flow is perceived by laterally positioned sensory LRO (sLRO) cells, which harbor non-motile cilia. In sLRO cells on the left side, flow-induced signaling triggers post-transcriptional repression of the multi-pathway antagonist dand5. Subsequently, the co-expressed Tgf-β growth factor Nodal1 is released from Dand5-mediated repression to induce left-sided gene expression. Interestingly, Xenopus sLRO cells have somitic fate, suggesting a connection between LR determination and somitogenesis. Here, we show that doublesex and mab3-related transcription factor 2 (Dmrt2), known to be involved in vertebrate somitogenesis, is required for LRO ciliogenesis and sLRO specification. In dmrt2 morphants, misexpression of the myogenic transcription factors tbx6 and myf5 at early gastrula stages preceded the misspecification of sLRO cells at neurula stages. myf5 morphant tadpoles also showed LR defects due to a failure of sLRO development. The gain of myf5 function reintroduced sLRO cells in dmrt2 morphants, demonstrating that paraxial patterning and somitogenesis are functionally linked to LR axis formation in Xenopus.

Keywords:  Xenopus; cilia; dmrt2; embryo; left-right asymmetry; myf5; paraxial patterning; somitogenesis

DOI:  https://doi.org/10.3389/fcell.2022.858272
Intern Med. 2022 Jul 14.

Kidney Histology Findings in a Patient with Autosomal Dominant Tubulointerstitial Kidney Disease Subtype Hepatocyte Nuclear Factor 1β.

Yuki Nakayama, Naoki Sawa, Tatsuya Suwabe, Masayuki Yamanouchi, Daisuke Ikuma, Hiroki Mizuno, Eiko Hasegawa, Junichi Hoshino, Akinari Sekine, Yuki Oba, Kei Kono, Keiichi Kinowaki, Kenichi Ohashi, Yutaka Yamaguchi, Kandai Nozu, Yoshifumi Ubara.

  We evaluated kidney histology in a 43-year-old woman with autosomal dominant tubulointerstitial kidney disease subtype hepatocyte nuclear factor 1β. Magnetic resonance imaging showed multiple cysts in the renal medullary area, and computed tomography showed hypoplasia of the pancreatic body and tail. A kidney biopsy showed thinning of the cortex, size reduction of glomerular tuft area, proximal tubule clustering, fibrosis around the tubules, loss of peritubular capillaries, and multilayered epithelial cells of cortical collecting ducts; this last finding was consistent with so-called medullary dysplasia specific to congenital disease, in which the renal pelvic epithelial cells enter the collecting duct.

Keywords:  autosomal dominant tubulointerstitial kidney disease (ADTKD); hepatocyte nuclear factor 1β (HNF1B); medullary dysplasia,

DOI:  https://doi.org/10.2169/internalmedicine.9364-22
Pediatr Pulmonol. 2022 Jul 13.

Psychological status of mothers of children with cystic fibrosis and primary ciliary dyskinesia.

Tugba Ramasli Gursoy, Tugba Sismanlar Eyuboglu, Ayse Tana Aslan, Nagehan Emiralioglu, Sevgi Pekcan, Eda Zeynep Buyukkaya, Melih Hangul, Mehmet Kose, Sebnem Soysal, Isil Irem Budakoglu.

   OBJECTIVES: We aimed to investigate depression, burnout, attitude, and burden of caregivers of children with cystic fibrosis (CF), and especially caregivers of children with primary ciliary dyskinesia (PCD) due to limited number of studies on this topic, and to compare them according to their children's clinical status.
METHODS: Clinical features and demographic data of children and their families were asked to caregivers in four pediatric pulmonology centers. Beck Depression Inventory, Maslach Burnout Inventory, Zarit Caregiver Burden Scale, and Parental Attitude Research Instrument were administered to caregivers in both groups. Results were compared between the two groups.
RESULTS: In total, 131 children with CF and 39 with PCD and their caregivers were involved in study. All primary caregivers were mothers in both groups. Depression, burnout, and burden scores of mothers of children with CF were significantly higher than mothers of children with PCD (p=0.017, p=0.024, p=0.038, respectively). Burnout was higher in both CF and PCD groups with low family income (p=0.022, p=0.034). Number of hospital visits in the previous six months was correlated with burnout in both CF and PCD groups (r=0.207, p=0.034; r=0.352, p=0.044).
CONCLUSIONS: Although mothers with children with CF have higher levels of depression, burnout, burden and negative attitudes towards children than mothers with children with PCD, these are also significantly high in mothers with children with PCD. Psychological problems of mothers of children with CF and PCD may increase with frequent hospital visits, hospitalizations, low family income, number of children, and chronic disease in another child. This article is protected by copyright. All rights reserved.

Keywords:  children; cystic fibrosis; mothers; primary ciliary dyskinesia; psychology

DOI:  https://doi.org/10.1002/ppul.26080
Inflammopharmacology. 2022 Jul 13.

NEK7: a new target for the treatment of multiple tumors and chronic inflammatory diseases.

Jin Wang, Simeng Chen, Min Liu, Min Zhang, Xiaoyi Jia.

  NIMA-related kinase 7 (NEK7) is a serine/threonine kinase, which is the smallest one in mammalian NEK family. At present, many studies have reported that NEK7 has a physiological role in regulating the cell cycle and promoting the mitotic process of cells. In recent years, an increasing number of studies have proposed that NEK7 is involved in the activation of the NLRP3 inflammasome. Under normal conditions, NEK7 is in a low activity state, while under pathological conditions, NEK7 is abnormally expressed and therefore plays a key role in the progression of multiple tumors and chronic inflammatory diseases. This review will concentrate on the mechanism of NEK7 participates in the process of mitosis and regulates the activation of NLRP3 inflammasome, the aberrant expression of NEK7 in a variety of tumors and chronic inflammatory diseases, and some potential inhibitors, which may provide some new ideas for the treatment of diverse tumors and chronic inflammatory diseases associated with NEK7.

Keywords:  Chronic inflammatory diseases; Mitosis; NEK7; NLRP3 inflammasome; Tumors

DOI:  https://doi.org/10.1007/s10787-022-01026-7