bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–01–22
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. The Clinical and Mutational Spectrum of 69 Turkish Children with Autosomal Recessive or Autosomal Dominant Polycystic Kidney Disease: A Multicenter Retrospective Cohort Study.
  2. The Relevance of the Imaging in Autosomal Dominant Polycystic Kidney Disease Management.
  3. Dual diagnosis of autosomal dominant polycystic kidney disease and sickle cell disease in a teenage male.
  4. Staged vs. simultaneous bilateral nephrectomy and kidney transplantation in patients with autosomal dominant polycystic kidney disease: Outcomes and costs.
  5. Drosophila transition fibers are essential for IFT-dependent ciliary elongation but not basal body docking and ciliary budding.
  6. Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.
  7. Combining Metformin and Drug-Loaded Kidney-Targeting Micelles for Polycystic Kidney Disease.
  8. Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation.
  9. PDE6D Mediates Trafficking of Prenylated Proteins NIM1K and UBL3 to Primary Cilia.
  10. Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia.
  11. Severe parental phenotype associates with hypertension in children with ADPKD.
  12. Ambroxol-enhanced ciliary beating via voltage-gated Ca2+ channels in mouse airway ciliated cells.
  1. Nephron. 2023 Jan 19. 1-14
    The Clinical and Mutational Spectrum of 69 Turkish Children with Autosomal Recessive or Autosomal Dominant Polycystic Kidney Disease: A Multicenter Retrospective Cohort Study.
    Ozum Tutal, Bora Gulhan, Emine Atayar, Selcuk Yuksel, Z Birsin Ozcakar, Oguz Soylemezoglu, Seha Saygili, Salim Caliskan, Mihriban Inozu, Esra Baskin, Ali Duzova, Mutlu Hayran, Rezan Topaloglu, Fatih Ozaltin.
       INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) is associated with pathogenic variants in the PKHD1 gene. Autosomal dominant polycystic kidney disease (ADPKD) is mainly associated with pathogenic variants in PKD1 or PKD2. The present study aimed to identify the clinical and genetic features of Turkish pediatric ARPKD and ADPKD patients.
    METHODS: This multicenter, retrospective cohort study included 21 genetically confirmed ARPKD and 48 genetically confirmed ADPKD patients from 7 pediatric nephrology centers. Demographic features, clinical, and laboratory findings at presentation and during 12-month intervals were recorded.
    RESULTS: The median age of the ARPKD patients at diagnosis was lower than the median age of ADPKD patients (10.5 months [range: 0-15 years] vs. 5.2 years [range: 0.1-16 years], respectively, [p = 0.014]). At the time of diagnosis, the median eGFR in the ARPKD patients was lower compared to that of ADPKD patients (81.6 [IQR: 28.7-110.5] mL/min/1.73 m2 and 118 [IQR: 91.2-139.8] mL/min/1.73 m2, respectively, [p = 0.0001]). In total, 11 (52.4%) ARPKD patients had malnutrition; 7 (33.3%) patients had growth retardation at presentation; and 4 (19%) patients had both malnutrition and growth retardation. At diagnosis, 8 (16.7%) of the ADPKD patients had malnutrition, and 5 (10.4%) patients had growth retardation. The malnutrition, growth retardation, and hypertension rates at diagnosis were higher in the ARPKD patients than the ADPKD patients (p = 0.002, p = 0.02, and p = 0.0001, respectively). ARPKD patients with malnutrition and growth retardation had worse renal survival compared to the patients without (p = 0.03 and p = 0.01). Similarly, ADPKD patients with malnutrition had worse renal survival compared to the patients without (p = 0.002). ARPKD patients with truncating variants had poorer 3- and 6-year renal outcome than those carrying non-truncating variants (p = 0.017).
    CONCLUSION: Based on renal survival analysis, type of genetic variant, growth retardation, and/or malnutrition at presentation were observed to be factors associated with progression to chronic kidney disease (CKD). Differentiation of ARPKD and ADPKD, and identification of the predictors of the development of CKD are vital for optimal management of patients with ARPKD or ADPKD.
    Keywords:  Autosomal dominant polycystic kidney disease; Autosomal recessive polycystic kidney disease; Chronic kidney disease; PKD1; PKD2; PKHD1; Prognosis
    DOI:  https://doi.org/10.1159/000528258
  2. Saudi J Kidney Dis Transpl. 2022 Jan-Feb;33(1):33(1): 218-220
    The Relevance of the Imaging in Autosomal Dominant Polycystic Kidney Disease Management.
    Francesca Finazzo, Gioacchino Li Cavoli, Rosalia Mongiovì, Luisa Bono, Angelo Ferrantelli, Angelo Tralongo.
      
    DOI:  https://doi.org/10.4103/1319-2442.367820
  3. Pediatr Nephrol. 2023 Jan 16.
    Dual diagnosis of autosomal dominant polycystic kidney disease and sickle cell disease in a teenage male.
    Quinn Stein, Kathleen Herman, Jennifer Deyo, Colleen McDonough, Michelle S Bloom, Asifhusen Mansuri.
       BACKGROUND: Sickle cell disease (SCD) and autosomal dominant polycystic kidney disease (ADPKD) are relatively common genetic conditions with considerable overlap in clinical presentation. In addition to similarities between the signs and symptoms in sickle cell nephropathy and ADPKD, more than half of SCD patients have kidney cysts. The co-occurrence of these two diseases has not been previously reported in the literature.
    CASE DIAGNOSIS/TREATMENT: A 16-year-old Black male with SCD had bilateral kidney enlargement and multiple simple cysts on ultrasound. Although kidney cysts are significantly more common in individuals affected with SCD, genetic testing with a broad kidney gene panel was performed to explore the possible presence of another underlying genetic cause of his cysts, in addition to SCD. A dual diagnosis of SCD and ADPKD was made following the identification of two copies of the common pathogenic sickle cell HBB variant (c.20A > T, p.Glu7Val) and a pathogenic missense variant in PKD1 (c.8311G > A, p.Glu2771Lys).
    CONCLUSIONS: SCD and ADPKD differ in pathophysiological mechanisms and treatment regimens. As such, it will be paramount for this teenager to be closely monitored for signs of diminished kidney function and to be co-managed as he transitions to adult care to ensure proper treatment and management. Early identification of individuals with both SCD and a co-occurring condition is crucial to ensuring proper clinical management. Furthermore, identifying and reporting additional patients with SCD and ADPKD dual diagnoses will help us to understand the co-occurring disease course and optimal treatments.
    Keywords:  Genetic testing; Kidney cysts; Polycystic kidney disease; Sickle cell disease
    DOI:  https://doi.org/10.1007/s00467-023-05873-6
  4. Can Urol Assoc J. 2022 Dec;16(12): 424-429
    Staged vs. simultaneous bilateral nephrectomy and kidney transplantation in patients with autosomal dominant polycystic kidney disease: Outcomes and costs.
    Andrew Rasmussen, Max A Levine, Moaath M Mandurah, Alp Sener, Patrick P Luke.
       INTRODUCTION: We sought to compare cost and safety outcomes of patients who received a kidney transplant and bilateral nephrectomy in either a simultaneous or staged approach.
    METHODS: We reviewed all adult patients with autosomal dominant polycystic kidney disease (ADPKD) who received a kidney transplant and underwent bilateral nephrectomy between 2008 and 2019. Patients were divided into two groups: staged (nephrectomy prior to transplant) and simultaneous (nephrectomy at the time of transplant). The primary outcome was cumulative cost of nephrectomy and transplantation ($CAD). We analyzed several secondary outcomes, including 90-day Clavien-Dindo complication rates.
    RESULTS: A total of 114 patients with ADPKD received a kidney transplant over 11 years. Of these, 28 patients underwent both nephrectomy and transplantation (10 staged, 18 simultaneous). More patients in the simultaneous group had a living donor transplant (83% vs. 0%, p<0.001). Creatinine clearance at one year/last followup did not differ between groups (p=0.12). With similar overall complication rates between groups, the transfusion rate was also similar between groups (simultaneous 50% vs. staged 40%, p=0.91). Total cost was lower in the simultaneous group ($23 775.33 CAD vs. $35 048.83 CAD, p<0.001), largely owing to a longer total length of stay in the staged group as compared to the simultaneous group (8.1 vs. 14.5 days, p<0.001).
    CONCLUSIONS: These data suggest that a simultaneous approach to bilateral nephrectomy and kidney transplantation provides potential cost savings with no adverse outcomes. This provides a rationale to investigate simultaneous nephrectomy and transplantation in the deceased donor setting.
    DOI:  https://doi.org/10.5489/cuaj.7816
  5. Curr Biol. 2023 Jan 11. pii: S0960-9822(22)01983-2. [Epub ahead of print]
    Drosophila transition fibers are essential for IFT-dependent ciliary elongation but not basal body docking and ciliary budding.
    Yanan Hou, Shirui Zheng, Zhimao Wu, Céline Augière, Véronique Morel, Elisabeth Cortier, Jean-Luc Duteyrat, Yingying Zhang, Huicheng Chen, Ying Peng, Bénédicte Durand, Qing Wei.
      Cilia are highly conserved organelles critical for animal development and perception. Dysfunction of cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies.1,2 Transition fibers (TFs) are striking ciliary base structures essential for cilia assembly. Vertebrates' TFs that originate from centriole distal appendages (DAs) mediate basal body docking to ciliary vesicles to initiate ciliogenesis and regulate the entry of ciliary proteins for axoneme assembly via intraflagellar transport (IFT) machinery.3 Although no distal appendages can be observed on Drosophila centrioles,4,5 three key TF proteins, FBF1, CEP164, and CEP89, have obvious homologs in Drosophila. We aimed to compare their functions with their mammalian counterparts in Drosophila ciliogenesis. Here, we show that all three proteins are localized like TF proteins at the ciliary base in both sensory neurons and spermatocytes, the only two types of ciliated cells in flies. Fbf1 and Cep89 are essential for the formation of IFT-dependent neuronal cilia, but Cep164 is dispensable for ciliogenesis in flies. Strikingly, none are required for basal body docking and transition zone (TZ) assembly in IFT-dependent neuronal cilia or IFT-independent spermatocyte cilia. Furthermore, we demonstrate that Unc is essential to recruit all three TF proteins and establish a hierarchical order, with Cep89 acting on Fbf1. Collectively, our results not only demonstrate that TF proteins are required for IFT-dependent ciliogenesis in Drosophila, in agreement with an evolutionarily conserved function of these proteins in regulating ciliary protein entry, but also that the basal body docking function of TFs has diverged during evolution.
    Keywords:  Cep164; Cep89; Fbf1; IFT; Unc; centriole; cilia; ciliopathies; distal appendages; transition zone
    DOI:  https://doi.org/10.1016/j.cub.2022.12.046
  6. J Magn Reson Imaging. 2023 Jan 16.
    Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.
    Hreedi Dev, Chenglin Zhu, Arman Sharbatdaran, Syed I Raza, Sophie J Wang, Dominick J Romano, Akshay Goel, Kurt Teichman, Mina C Moghadam, George Shih, Jon D Blumenfeld, Daniil Shimonov, James M Chevalier, Martin R Prince.
       BACKGROUND: Total kidney volume (TKV) is an important biomarker for assessing kidney function, especially for autosomal dominant polycystic kidney disease (ADPKD). However, TKV measurements from a single MRI pulse sequence have limited reproducibility, ± ~5%, similar to ADPKD annual kidney growth rates.
    PURPOSE: To improve TKV measurement reproducibility on MRI by extending artificial intelligence algorithms to automatically segment kidneys on T1-weighted, T2-weighted, and steady state free precession (SSFP) sequences in axial and coronal planes and averaging measurements.
    STUDY TYPE: Retrospective training, prospective testing.
    SUBJECTS: Three hundred ninety-seven patients (356 with ADPKD, 41 without), 75% for training and 25% for validation, 40 ADPKD patients for testing and 17 ADPKD patients for assessing reproducibility.
    FIELD STRENGTH/SEQUENCE: T2-weighted single-shot fast spin echo (T2), SSFP, and T1-weighted 3D spoiled gradient echo (T1) at 1.5 and 3T.
    ASSESSMENT: 2D U-net segmentation algorithm was trained on images from all sequences. Five observers independently measured each kidney volume manually on axial T2 and using model-assisted segmentations on all sequences and image plane orientations for two MRI exams in two sessions separated by 1-3 weeks to assess reproducibility. Manual and model-assisted segmentation times were recorded.
    STATISTICAL TESTS: Bland-Altman, Schapiro-Wilk (normality assessment), Pearson's chi-squared (categorical variables); Dice similarity coefficient, interclass correlation coefficient, and concordance correlation coefficient for analyzing TKV reproducibility. P-value < 0.05 was considered statistically significant.
    RESULTS: In 17 ADPKD subjects, model-assisted segmentations of axial T2 images were significantly faster than manual segmentations (2:49 minute vs. 11:34 minute), with no significant absolute percent difference in TKV (5.9% vs. 5.3%, P = 0.88) between scans 1 and 2. Absolute percent differences between the two scans for model-assisted segmentations on other sequences were 5.5% (axial T1), 4.5% (axial SSFP), 4.1% (coronal SSFP), and 3.2% (coronal T2). Averaging measurements from all five model-assisted segmentations significantly reduced absolute percent difference to 2.5%, further improving to 2.1% after excluding an outlier.
    DATA CONCLUSION: Measuring TKV on multiple MRI pulse sequences in coronal and axial planes is practical with deep learning model-assisted segmentations and can improve TKV measurement reproducibility more than 2-fold in ADPKD.
    EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.
    Keywords:  artificial intelligence; autosomal dominant polycystic kidney disease; kidney volume; machine learning
    DOI:  https://doi.org/10.1002/jmri.28593
  7. Cell Mol Bioeng. 2023 Feb;16(1): 55-67
    Combining Metformin and Drug-Loaded Kidney-Targeting Micelles for Polycystic Kidney Disease.
    Kairui Jiang, Yi Huang, Eun Ji Chung.
       Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that leads to eventual renal failure. Metformin (MET), an AMP-activated protein kinase (AMPK) activator already approved for type 2 diabetes, is currently investigated for ADPKD treatment. However, despite high tolerability, MET showed varying therapeutic efficacy in preclinical ADPKD studies. Thus, newer strategies have combined MET with other ADPKD small molecule drug candidates, thereby targeting multiple ADPKD-associated signaling pathways to enhance therapeutic outcomes through potential drug synergy. Unfortunately, the off-target side effects caused by these additional drug candidates pose a major hurdle. To address this, our group has previously developed kidney-targeting peptide amphiphile micelles (KMs), which displayed significant kidney accumulation in vivo, for delivering drugs to the site of the disease.
    Methods: To mitigate the adverse effects of ADPKD drugs and evaluate their therapeutic potential in combination with MET, herein, we loaded KMs with ADPKD drug candidates including salsalate, octreotide, bardoxolone methyl, rapamycin, tolvaptan, and pioglitazone, and tested their in vitro therapeutic efficacy when combined with free MET. Specifically, after determining the 40% inhibitory concentration for each drug (IC40), the size, morphology, and surface charge of drug-loaded KMs were characterized. Next, drug-loaded KMs were applied in combination with MET to treat renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice in 2D proliferation and 3D cyst model.
    Results: MET combined with all drug-loaded KMs demonstrated significantly enhanced efficacy as compared to free drugs in inhibiting cell proliferation and cyst growth. Notably, synergistic effects were found for MET and KMs loaded with either salsalate or rapamycin as determined by Bliss synergy scores.
    Conclusion: Together, we show drug synergy using drug-loaded nanoparticles and free MET for the first time and present a novel nanomedicine-based combinatorial therapeutic approach for ADPKD with enhanced efficacy.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00753-9.
    Keywords:  Autosomal dominant polycystic kidney disease; Combinatorial therapy; Metformin; Nanoparticle
    DOI:  https://doi.org/10.1007/s12195-022-00753-9
  8. Bone Rep. 2023 Jun;18 101655
    Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation.
    Dalia Zubidat, Christian Hanna, Amarjyot K Randhawa, Byron H Smith, Maroun Chedid, Daniel-Hasan N Kaidbay, Luca Nardelli, Yaman G Mkhaimer, Reem M Neal, Charles D Madsen, Sarah R Senum, Adriana V Gregory, Timothy L Kline, Ziad M Zoghby, Stephen M Broski, Naim S Issa, Peter C Harris, Vicente E Torres, Jad G Sfeir, Fouad T Chebib.
      ADPKD is caused by pathogenic variants in PKD1 or PKD2, encoding polycystin-1 and -2 proteins. Polycystins are expressed in osteoblasts and chondrocytes in animal models, and loss of function is associated with low bone mineral density (BMD) and volume. However, it is unclear whether these variants impact bone strength in ADPKD patients. Here, we examined BMD in ADPKD after kidney transplantation (KTx). This retrospective observational study retrieved data from adult patients who received a KTx over the past 15 years. Patients with available dual-energy X-ray absorptiometry (DXA) of the hip and/or lumbar spine (LS) post-transplant were included. ADPKD patients (n = 340) were matched 1:1 by age (±2 years) at KTx and sex with non-diabetic non-ADPKD patients (n = 340). Patients with ADPKD had slightly higher BMD and T-scores at the right total hip (TH) as compared to non-ADPKD patients [BMD: 0.951 vs. 0.897, p < 0.001; T-score: -0.62 vs. -0.99, p < 0.001] and at left TH [BMD: 0.960 vs. 0.893, p < 0.001; T-score: -0.60 vs. -1.08, p < 0.001], respectively. Similar results were found at the right femoral neck (FN) between ADPKD and non-ADPKD [BMD: 0.887 vs. 0.848, p = 0.001; T-score: -1.20 vs. -1.41, p = 0.01] and at left FN [BMD: 0.885 vs. 0.840, p < 0.001; T-score: -1.16 vs. -1.46, p = 0.001]. At the LS level, ADPKD had a similar BMD and lower T-score compared to non-ADPKD [BMD: 1.120 vs. 1.126, p = 0.93; T-score: -0.66 vs. -0.23, p = 0.008]. After adjusting for preemptive KTx, ADPKD patients continued to have higher BMD T-scores in TH and FN. Our findings indicate that BMD by DXA is higher in patients with ADPKD compared to non-ADPKD patients after transplantation in sites where cortical but not trabecular bone is predominant. The clinical benefit of the preserved cortical bone BMD in patients with ADPKD needs to be explored in future studies.
    Keywords:  ADPKD; Bone; Mineral metabolism; Transplantation
    DOI:  https://doi.org/10.1016/j.bonr.2023.101655
  9. Cells. 2023 Jan 13. pii: 312. [Epub ahead of print]12(2):
    PDE6D Mediates Trafficking of Prenylated Proteins NIM1K and UBL3 to Primary Cilia.
    Siebren Faber, Stef J F Letteboer, Katrin Junger, Rossano Butcher, Trinadh V Satish Tammana, Sylvia E C van Beersum, Marius Ueffing, Rob W J Collin, Qin Liu, Karsten Boldt, Ronald Roepman.
      Mutations in PDE6D impair the function of its cognate protein, phosphodiesterase 6D (PDE6D), in prenylated protein trafficking towards the ciliary membrane, causing the human ciliopathy Joubert Syndrome (JBTS22) and retinal degeneration in mice. In this study, we purified the prenylated cargo of PDE6D by affinity proteomics to gain insight into PDE6D-associated disease mechanisms. By this approach, we have identified a specific set of PDE6D-interacting proteins that are involved in photoreceptor integrity, GTPase activity, nuclear import, or ubiquitination. Among these interacting proteins, we identified novel ciliary cargo proteins of PDE6D, including FAM219A, serine/threonine-protein kinase NIM1 (NIM1K), and ubiquitin-like protein 3 (UBL3). We show that NIM1K and UBL3 localize inside the cilium in a prenylation-dependent manner. Furthermore, UBL3 also localizes in vesicle-like structures around the base of the cilium. Through affinity proteomics of UBL3, we confirmed its strong interaction with PDE6D and its association with proteins that regulate small extracellular vesicles (sEVs) and ciliogenesis. Moreover, we show that UBL3 localizes in specific photoreceptor cilium compartments in a prenylation-dependent manner. Therefore, we propose that UBL3 may play a role in the sorting of proteins towards the photoreceptor outer segment, further explaining the development of PDE6D-associated retinal degeneration.
    Keywords:  FAM219A; NIM1K; PDE6D; UBL3; cilium; photoreceptor; prenylation; protein trafficking
    DOI:  https://doi.org/10.3390/cells12020312
  10. Mol Biol Cell. 2023 Jan 18. mbcE22100473
    Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia.
    Vivek Reddy Palicharla, Sun-Hee Hwang, Bandarigoda N Somatilaka, Emilie Legué, Issei S Shimada, Nicole E Familiari, Vanna M Tran, Jeffrey B Woodruff, Karel F Liem, Saikat Mukhopadhyay.
      The primary cilium is a nexus for cell signaling and relies on specific protein trafficking for function. The tubby family protein-TULP3 transports integral membrane proteins into cilia through interactions with the intraflagellar transport complex-A (IFT-A) and phosphoinositides. We previously showed that short motifs called ciliary localization sequences (CLSs) are necessary and sufficient for TULP3-dependent ciliary trafficking of transmembrane cargoes. However, the mechanisms by which TULP3 regulates ciliary compartmentalization of non-integral, membrane-associated proteins, and if such trafficking requires TULP3-dependent CLSs is unknown. Here we show that TULP3 is required for ciliary transport of the Joubert syndrome-linked palmitoylated GTPase-ARL13B through a CLS. An N-terminal amphipathic helix, preceding the GTPase domain of ARL13B, couples with the TULP3 tubby domain for ciliary trafficking, irrespective of palmitoylation. ARL13B transport requires TULP3 binding to IFT-A but not to phosphoinositides, indicating strong membrane-proximate interactions, unlike transmembrane cargo transport requiring both properties of TULP3. TULP3-mediated trafficking of ARL13B also regulates ciliary enrichment of farnesylated and myristoylated downstream effectors of ARL13B. The lipidated cargoes show distinctive depletion kinetics from kidney epithelial cilia with relation to Tulp3 deletion-induced renal cystogenesis. Overall, these findings indicate an expanded role of the tubby domain in capturing analogous helical secondary structural motifs from diverse cargoes.
    DOI:  https://doi.org/10.1091/mbc.E22-10-0473
  11. Pediatr Nephrol. 2023 Jan 16.
    Severe parental phenotype associates with hypertension in children with ADPKD.
    Nathalie Demoulin, Elliott Van Regemorter, Karin Dahan, Charlotte Hougardy, Johann Morelle, Valentine Gillion, Nadejda Ranguelov, Nathalie Godefroid.
       BACKGROUND: Early detection of hypertension in children with autosomal polycystic kidney disease (ADPKD) may be beneficial, but screening children at risk of ADPKD remains controversial. We investigated determinants of hypertension in children with ADPKD to help identify a subgroup of children at risk of ADPKD for whom screening for the disease and/or its complications would be more relevant.
    METHODS: In a retrospective study including consecutive children with ADPKD aged 5-18 years and followed at Saint-Luc Hospital Brussels between 2006 and 2020, we investigated the potential association between genotype, clinical characteristics and parental phenotype, and presence of hypertension. Hypertension was defined as blood pressure > P95 during 24-h ambulatory monitoring or anti-hypertensive therapy use. Parental phenotype was considered severe based on age at kidney failure, Mayo Clinic Imaging Classification and rate of eGFR decline.
    RESULTS: The study enrolled 55 children with ADPKD (mean age 9.9 ± 2.2 years, 45% male), including 44 with a PKD1 mutation and 5 with no mutation identified. Nine (16%) children had hypertension. Hypertension in children was associated with parental phenotype severity (8/27 (30%) children with severe parental phenotype vs. 1/23 (4%) children with non-severe parental phenotype (p = 0.03)) and height-adjusted bilateral nephromegaly (6/9 (67%) children with bilateral nephromegaly vs. 3/44 (7%) children without bilateral nephromegaly (p < 0.001)).
    CONCLUSIONS: Severe parental phenotype is associated with higher prevalence of hypertension in children with ADPKD. Hence, children of parents with severe ADPKD phenotype may be those who will most benefit from screening of the disease and/or yearly BP measures. A higher resolution version of the Graphical abstract is available as Supplementary information.
    Keywords:  ABPM; Autosomal dominant polycystic kidney disease; Nephromegaly; PKD1
    DOI:  https://doi.org/10.1007/s00467-022-05870-1
  12. Eur J Pharmacol. 2023 Jan 12. pii: S0014-2999(23)00007-9. [Epub ahead of print]941 175496
    Ambroxol-enhanced ciliary beating via voltage-gated Ca2+ channels in mouse airway ciliated cells.
    Daichi Saito, Chihiro Suzuki, Saori Tanaka, Shigekuni Hosogi, Kotoku Kawaguchi, Shinji Asano, Shohta Okamoto, Makoto Yasuda, Shigeru Hirano, Toshio Inui, Yoshinori Marunaka, Takashi Nakahari.
      Ambroxol (ABX) facilitates the mucociliary clearance (MC) by enhancing ciliary beating in airways. In this study, we focused on airway ciliary beating enhanced by ABX. However, little is known about the ABX-stimulated Ca2+ signalling activating airway ciliary beating. Airway ciliated cells isolated from mice lungs were observed by a high-speed video microscope, and the activities of beating cilia were assessed by CBF (ciliary beat frequency) and CBD (ciliary bend distance, an index of amplitude). ABX (10 μM) enhanced the CBF and CBD by 30%, and the enhancement was inhibited by nifedipine (20 μM, a L-type voltage-gated Ca2+ channel (CaV) inhibitor), or a Ca2+-free solution (approximately 50%). Pre-treatment with BAPTA-AM (10 μM, a chelator of intracellular Ca2+) abolished ABX-stimulated increases in CBF, CBD and [Ca2+]i. Thus, ABX increases [Ca2+]i (intracellular Ca2+ concentration) by stimulating Ca2+ release from the internal stores and nifedipine-sensitive Ca2+ entry. A previous study demonstrated the expression of CaV1.2 in airway cilia. ABX enhanced CBF, CBD and [Ca2+]i even in a high extracellular K+ concentration (155.5 mM), suggesting that it activates CaV1.2 except by depolarization. These enhancements were inhibited by nifedipine. In conclusion, ABX, which increases [Ca2+]i by stimulating Ca2+ release from internal stores and Ca2+ entry through CaV1.2s, enhanced CBF and CBD in airway ciliated cells. ABX is a novel agonist that modulates CaV1.2 of airway beating cilia to enhance CBF and CBD.
    Keywords:  Airway ciliary beating; Ambroxol; Ca(V); Intracellular Ca(2+) concentration; Nifedipine
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175496
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