bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022‒11‒20
thirteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Incisional hernia by liver cysts.
  2. Tolvaptan ameliorated kidney function for one elderly autosomal dominant polycystic kidney disease patient: A case report.
  3. Drug management of autosomal dominant polycystic kidney disease.
  4. Renin-angiotensin system activation: may it increase frequency of obstructive sleep apnea in patients with autosomal dominant polycystic kidney disease?
  5. Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.
  6. Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-β1 signaling.
  7. Renoprotective effects of docosahexaenoic acid in cats with early chronic kidney disease due to polycystic kidney disease: a pilot study.
  8. Cilia-Mediated Insulin/Akt and ST2/JNK Signaling Pathways Regulate the Recovery of Muscle Injury.
  9. Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
  10. Α γ-tubulin complex-dependent pathway suppresses ciliogenesis by promoting cilia disassembly.
  11. Editorial: Genetics and mechanism of ciliopathies.
  12. Glucocorticoid in Combination with a TNF-α Inhibitor: Treatment of Deep Vein Thrombosis in a Patient with Behçet's Disease.
  13. A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins.
  1. Clin Case Rep. 2022 Nov;10(11): e6491
    Incisional hernia by liver cysts.
    Mauro Giuffrè, Martina Budel, Paola Martingano, Lory Saveria Crocè.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease and is associated with cystic manifestation in the liver. Patients with ADPKD are at higher risk for hernias, here we present an image of an incisional hernia full of multiple liver cysts.
    Keywords:  abdominal hernia; autosomal dominant polycystic kidney disease; hernia; incisional hernia; liver cysts
    DOI:  https://doi.org/10.1002/ccr3.6491
  2. World J Clin Cases. 2022 Nov 06. 10(31): 11500-11507
    Tolvaptan ameliorated kidney function for one elderly autosomal dominant polycystic kidney disease patient: A case report.
    Li Zhou, Yan Tian, Liang Ma, Wen-Ge Li.
      BACKGROUND: Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts within the kidneys. Disease progress of some patients often occurs at the early stage. Thus, managing and controlling disease progress is important to slow the kidney function decline especially for the patient with other disorders.CASE SUMMARY: One 80-year-old male autosomal dominant polycystic kidney disease (ADPKD) patient with chronic kidney disease and other clinical disorders was treated with tolvaptan and edoxaban. Estimated glomerular filtration rate, creatinine and uric acid were monitored during the treatment. In addition, the whole exome sequencing was performed to screen ADPKD genetic variants. The kidney function decline was prevented after using tolvaptan and edoxaban treatment and in the meantime, a venous thromboembolism was removed and leg and pedal edema were alleviated. One mutation c.10102G>A /p.D3368N in the PKD1 gene was identified.
    CONCLUSION: Tolvaptan combined with edoxaban administration could delay kidney function decline and eliminate the edema caused by the thromboembolism.
    Keywords:  Autosomal dominant polycystic kidney disease; Case report; Chronic kidney disease; Deep vein thrombosis; Tolvaptan
    DOI:  https://doi.org/10.12998/wjcc.v10.i31.11500
  3. Aust Prescr. 2022 Oct;45(5): 167-170
    Drug management of autosomal dominant polycystic kidney disease.
    Thiveya Theivendran, Alister Ramachandran, Gopi Rangan.
      Autosomal dominant polycystic kidney disease is the most common genetic kidney disease affecting adults. Approximately 60% of patients develop kidney failure by 60 years of age due to slowly expanding kidney cysts. A healthy lifestyle and rigorous control of blood pressure slow kidney cyst growth. These interventions can be effective in reducing progression to kidney failure and cardiovascular disease, especially if started in early adulthood. Tolvaptan, a vasopressin receptor antagonist, slows kidney cyst growth and the decline in the estimated glomerular filtration rate by 1 mL/minute/1.73 m2 per year. It is indicated in patients with chronic kidney disease who are at high risk of progression to kidney failure. Chronic kidney pain is common and can be managed with analgesics, and input from pain specialists if refractory.
    Keywords:  autosomal dominant polycystic kidney disease; hypertension; pain; tolvaptan
    DOI:  https://doi.org/10.18773/austprescr.2022.052
  4. Sleep Breath. 2022 Nov 14.
    Renin-angiotensin system activation: may it increase frequency of obstructive sleep apnea in patients with autosomal dominant polycystic kidney disease?
    Serkan Feyyaz Yalin, Ersan Atahan, Sule Gundogdu, Ergun Parmaksiz, Meral Mese, Sinan Trabulus, Birsen Mutlu, Mehmet Riza Altiparmak.
      PURPOSE: Renin-angiotensin system (RAS) hyperactivity is a common entity in both autosomal dominant polycystic kidney disease (ADPKD) and obstructive sleep apnea (OSA). We aimed to investigate the frequency of OSA in adults with ADPKD either with stages 3-4 or stages 1-2 chronic kidney disease (CKD) and evaluate the effect of RAS blockade on OSA in these patients.METHODS: This is a comparative, prospective, two-center clinical study. Eligible patients with ADPKD were enrolled in a polysomnography (PSG) study. Presence of OSA in patients with ADPKD was compared with individuals who underwent polisomnography study due to OSA symptoms. A subgroup analysis was performed in terms of the presence of OSA in ADPKD with eGFR values lower or higher than 60 ml/min/1.73 m2 (stages 3-4 and stages 1-2 CKD, respectively).
    RESULTS: Frequency of OSA (65%) was higher than in the general population and similar between the two groups (p = 0.367). Patients with ADPKD and eGFR ≥ 60 ml/min/1.73 m2 presented a similar frequency of OSA to the control group (p = 0.759). However, OSA was significantly more frequent in ADPKD with eGFR < 60 ml/min/1.73 m2 (p = 0.018). Subgroup analysis revealed that presence of OSA also was significantly higher in ADPKD with lower eGFR levels (eGFR < 60 ml/min/1.73 m2 and eGFR > 60 ml/min/1.73 m2) 14/17 (82%) and 12/23 (52%), respectively (p: 0.048).
    CONCLUSION: As kidney disease progresses, uremia and related factors of renal failure rather than RAS activation seem to play a more important role for the development of OSA in patients with ADPKD.
    Keywords:  Autosomal dominant polycystic kidney disease; Obstructive sleep apnea syndrome; Polysomnography; Renin-angiotensin system
    DOI:  https://doi.org/10.1007/s11325-022-02742-8
  5. J Med Chem. 2022 Nov 17.
    Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.
    Bowen Yang, Haoran Zhang, Na Li, Lixin Gao, Hong Jiang, Weijuan Kan, Haoxing Yuan, Jia Li, Dongmei Zhao, Bing Xiong, Yubo Zhou, Dong Guo, Tongchao Liu.
      Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC50 value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin-Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01334
  6. Cell Tissue Res. 2022 Nov 15.
    Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-β1 signaling.
    Farideh Amirrad, Gregory A Fishbein, Robert A Edwards, Surya M Nauli.
      Autosomal dominant polycystic kidney disease (PKD) is a hereditary kidney disorder which can affect cardiovascular system. Cardiac hypertrophy and cardiomyopathy in PKD have been reported by echocardiography analyses, but histopathology analyses of human PKD hearts have never been examined. The current studies evaluated human heart tissues from five subjects without PKD (non-PKD) and five subjects with PKD. Our histopathology data of human PKD hearts showed an increased extracellular matrix associated with cardiac hypertrophy and fibrosis. Hypertrophy- and fibrosis-associated pathways involving abnormal cardiac structure were next analyzed. We found that human PKD myocardium was infiltrated by inflammatory macrophage M1 and M2; expression of transforming growth factor (TGF-β1) and its receptor were upregulated with overexpression of pSmad3 and β-catenin. Because patients with PKD have an abnormal kidney function that could potentially affect heart structure, we used a heart-specific PKD mouse model to validate that cardiac hypertrophy and fibrosis were independent from polycystic kidney. In summary, our data show that hearts from human PKD were characterized by hypertrophy, interstitial fibrosis, perivascular fibrosis, and conduction system fibrosis with upregulated TGF-β1 and its receptor. We suggest that such structural abnormalities may predispose to systolic and diastolic cardiac dysfunction in the PKD myocardium.
    Keywords:  Fibrosis; Hypertrophy; Kidney disorder
    DOI:  https://doi.org/10.1007/s00441-022-03704-y
  7. J Feline Med Surg. 2022 Nov 16. 1098612X221136815
    Renoprotective effects of docosahexaenoic acid in cats with early chronic kidney disease due to polycystic kidney disease: a pilot study.
    Saori Kobayashi, Masataka Kawarasaki, Ayami Aono, Junko Cho, Tomoaki Hashimoto, Reeko Sato.
      OBJECTIVES: Lipids containing n-3 fatty acids have been reported to have protective effects on renal function, with docosahexaenoic acid (DHA) expected to be particularly effective. However, no reports have demonstrated the renoprotective effects of DHA-enriched lipids in cats with chronic kidney disease (CKD). Therefore, the aim of this pilot study was to examine the renoprotective effects of DHA-enriched fish oil in cats.METHODS: Five healthy cats and five cats with early non-azotaemic CKD due to autosomal dominant polycystic kidney disease (PKD) were orally administered DHA-enriched fish oil in liquid form (250 or 500 mg/kg body weight [BW] and 250 mg/kg BW of DHA, respectively) for 28 days. Inappropriately dilute urine and markedly increased urinary N-acetyl-d-glucosamine (NAG) index were detected in cats with PKD before DHA-enriched fish oil administration. Changes in the fatty acid composition ratio in the blood of all 10 cats were assessed after orally administering 250 mg/kg of DHA.
    RESULTS: Post-administration, no adverse clinical effects were observed, and blood and urine tests were within the reference intervals in healthy cats. Cats with PKD showed significantly decreased serum symmetric dimethylarginine (SDMA), urine protein:creatinine ratio (UPC) and urinary NAG index at post-administration. Furthermore, oral administration of DHA-enriched fish oils significantly decreased the blood concentration ratio of arachidonic acid (AA) in cats with PKD post-administration. Furthermore, the concentration ratio of DHA in the blood significantly increased in both healthy cats and cats with PKD, and the DHA:AA ratio also increased.
    CONCLUSIONS AND RELEVANCE: Oral administration of DHA-enriched fish oils for 28 days significantly decreased blood AA levels and significantly increased DHA concentration and DHA:AA ratios in cats with PKD, and improved the SDMA, UPC and urinary NAG index, suggesting its potential for renoprotective effects in cats with early non-azotaemic CKD due to PKD.
    Keywords:  DHA; Potential renoprotective effects; docosahexaenoic acid; early non-azotaemic CKD; polycystic kidney disease
    DOI:  https://doi.org/10.1177/1098612X221136815
  8. Adv Sci (Weinh). 2022 Nov 14. e2202632
    Cilia-Mediated Insulin/Akt and ST2/JNK Signaling Pathways Regulate the Recovery of Muscle Injury.
    Daishi Yamakawa, Junya Tsuboi, Kousuke Kasahara, Chise Matsuda, Yuhei Nishimura, Tatsuya Kodama, Naoyuki Katayama, Masatoshi Watanabe, Masaki Inagaki.
      Following injury, skeletal muscle regenerates but fatty tissue accumulation is seen in aged muscle or muscular dystrophies. Fibro/adipogenic progenitors (FAPs) are key players in these events; however, the effect of primary cilia on FAPs remains unclear. Here, it is reported that genetic ablation of trichoplein (TCHP), a ciliary regulator, induces ciliary elongation on FAPs after injury, which promotes muscle regeneration while inhibiting adipogenesis. The defective adipogenic differentiation of FAPs is attributed to dysfunction of cilia-dependent lipid raft dynamics, which is critical for insulin/Akt signaling. It is also found that interleukin (IL) 13 is substantially produced by intramuscular FAPs, which are upregulated by ciliary elongation and contribute to regeneration. Mechanistically, upon injury, long cilia excessively activate the IL33/ST2/JNK axis to enhance IL13 production, facilitating myoblast proliferation and M2 macrophage polarization. The results indicate that FAPs organize the regenerative responses to skeletal muscle injury via cilia-mediated insulin/Akt and ST2/JNK signaling pathways.
    Keywords:  adipogenesis; fibro/adipogenic progenitors; interleukin 13; interleukin 33; lipid raft; primary cilia; skeletal muscle regeneration
    DOI:  https://doi.org/10.1002/advs.202202632
  9. J Cell Biol. 2023 Jan 02. pii: e202203019. [Epub ahead of print]222(1):
    Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
    Olesia Ignatenko, Satu Malinen, Sofiia Rybas, Helena Vihinen, Joni Nikkanen, Aleksander Kononov, Eija S Jokitalo, Gulayse Ince-Dunn, Anu Suomalainen.
      Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.
    DOI:  https://doi.org/10.1083/jcb.202203019
  10. Cell Rep. 2022 Nov 15. pii: S2211-1247(22)01513-3. [Epub ahead of print]41(7): 111642
    Α γ-tubulin complex-dependent pathway suppresses ciliogenesis by promoting cilia disassembly.
    Sahana Shankar, Zi-Ting Hsu, Artur Ezquerra, Chien-Chien Li, Tzu-Lun Huang, Etienne Coyaud, Ricardo Viais, Cédric Grauffel, Brian Raught, Carmay Lim, Jens Lüders, Su-Yi Tsai, Kuo-Chiang Hsia.
      The primary cilium, a microtubule-based sensory organelle, undergoes cycles of assembly and disassembly that govern the cell cycle progression critical to cell proliferation and differentiation. Although cilia assembly has been studied extensively, the molecular mechanisms underlying cilia disassembly are less well understood. Here, we uncover a γ-tubulin ring complex (γ-TuRC)-dependent pathway that promotes cilia disassembly and thereby prevents cilia formation. We further demonstrate that Kif2A, a kinesin motor that bears microtubule-depolymerizing activity, is recruited to the cilium basal body in a γ-TuRC-dependent manner. Our mechanistic analyses show that γ-TuRC specifically recruits Kif2A via the GCP2 subunit and its binding partner Mzt2. Hence, despite the long-standing view that γ-TuRC acts mainly as a microtubule template, we illustrate that its functional heterogeneity at the basal body facilitates both microtubule nucleation and Kif2A recruitment-mediated regulation of ciliogenesis, ensuring cell cycle progression.
    Keywords:  CP: Molecular biology; cell cycle; ciliogenesis; kinesin motor; microtubule; primary cilium; γ-tubulin ring complex
    DOI:  https://doi.org/10.1016/j.celrep.2022.111642
  11. Front Genet. 2022 ;13 1067168
    Editorial: Genetics and mechanism of ciliopathies.
    Steven Lim Cho Pei, Brian Hon Yin Chung.
      
    Keywords:  cilia; ciliopathies; dynein; exome sequencing; primary ciliary dyskinesia; single nucleotide polymorphisms
    DOI:  https://doi.org/10.3389/fgene.2022.1067168
  12. Intern Med. 2022 Nov 16.
    Glucocorticoid in Combination with a TNF-α Inhibitor: Treatment of Deep Vein Thrombosis in a Patient with Behçet's Disease.
    Mitsumasa Okano, Katsuhiko Yoneda, Yoshihide Ichise, Sentaro Kusuhara, Naokazu Muramae, Kenta Mori, Kazunori Otsui, Kazuhiko Sakaguchi.
      A 38-year-old man with deep vein thrombosis associated with Behçet's disease (BD) was admitted to our hospital due to worsening symptoms despite the initiation of direct oral anticoagulants (DOACs). Administration of oral prednisolone and an intravenous anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody dramatically improved his symptoms. In addition, he was incidentally diagnosed with autosomal dominant polycystic kidney disease, which increases the risk of aortic aneurysms. BD also increases the risk of aortic aneurysms. This case suggests that immunosuppressive treatment is effective in patients with inflammation-related DOAC-refractory venous thrombosis who also suffer from BD.
    Keywords:  Behçet's disease; anti-tumor necrosis factor-alpha monoclonal antibody; deep vein thrombosis; immunosuppressive treatment
    DOI:  https://doi.org/10.2169/internalmedicine.0209-22
  13. Nat Commun. 2022 Nov 12. 13(1): 6889
    A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins.
    Devendra Kumar Maurya, Anna Berghard, Staffan Bohm.
      Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion channels. Mechanisms regulating trafficking and localization of these proteins in the dendrite are unknown. By lectin/immunofluorescence staining and in vivo correlative light-electron microscopy (CLEM), we identify a retinitis pigmentosa-2 (RP2), ESCRT-0 and synaptophysin-containing multivesicular organelle that is not part of generic recycling/degradative/exosome pathways. The organelle's intraluminal vesicles contain the olfactory transduction proteins except for Golf subunits Gγ13 and Gβ1. Instead, Gβ1 colocalizes with RP2 on the organelle's outer membrane. The organelle accumulates in response to stimulus deprivation, while odor stimuli or adenylate cyclase activation cause outer membrane disintegration, release of intraluminal vesicles, and RP2/Gβ1 translocation to the base of olfactory cilia. Together, these findings reveal the existence of a dendritic organelle that mediates both stimulus-regulated storage of olfactory ciliary transduction proteins and membrane-delimited sorting important for G protein heterotrimerization.
    DOI:  https://doi.org/10.1038/s41467-022-34604-y
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