bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–08–14
nine papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency-Related Polycystic Kidney Disease.
  2. Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency.
  3. Prevalence of polycystic kidney disease in Persian and Persian-related cats in western Mexico.
  4. Regulation and Function of Calcium in the Cilium.
  5. Primary cilia and PTH1R interplay in the regulation of osteogenic actions.
  6. PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion.
  7. CAROLI'S SYNDROME WITH AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE ON FETAL MRI: A CASE REPORT.
  8. A transgenic zebrafish for in vivo visualization of cilia.
  9. Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length.
  1. J Am Soc Nephrol. 2022 Aug 12. pii: ASN.2021111455. [Epub ahead of print]
    KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency-Related Polycystic Kidney Disease.
    Gyuyeong Rah, Hwayeon Cha, Joohee Kim, Jieun Song, Hyunho Kim, Yun Kyu Oh, Curie Ahn, Minyong Kang, Jongmin Kim, Kyung Hyun Yoo, Min Jung Kim, Hyuk Wan Ko, Je Yeong Ko, Jong Hoon Park.
       BACKGROUND: Ciliogenesis-associated kinase 1 (CILK1) is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in CILK1 cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown.
    METHODS: To examine whether CILK1 deficiency causes PKD accompanied by abnormal cilia, we generated mice with deletion of Cilk1 in cells of the renal collecting duct. A yeast two-hybrid system and coimmunoprecipitation (co-IP) were used to identify a novel regulator, kinesin light chain-3 (KLC3), of ciliary trafficking and cyst progression in the Cilk1-deficient model. Immunocytochemistry and co-IP were used to examine the effect of KLC3 on ciliary trafficking of the IFT-B complex and EGFR. We evaluated the effects of these genes on ciliary trafficking and cyst progression by modulating CILK1 and KLC3 expression levels.
    RESULTS: CILK1 deficiency leads to PKD accompanied by abnormal ciliary trafficking. KLC3 interacts with CILK1 at cilia bases and is increased in cyst-lining cells of CILK1-deficient mice. KLC3 overexpression promotes ciliary recruitment of IFT-B and EGFR in the CILK1 deficiency condition, which contributes to the ciliary defect in cystogenesis. Reduction in KLC3 rescued the ciliary defects and inhibited cyst progression caused by CILK1 deficiency.
    CONCLUSIONS: Our findings suggest that CILK1 deficiency in renal collecting ducts leads to PKD and promotes ciliary trafficking via increased KLC3.
    Keywords:  CILK1; KLC3; PKD; cilia; cyst
    DOI:  https://doi.org/10.1681/ASN.2021111455
  2. Int J Mol Sci. 2022 Jul 31. pii: 8499. [Epub ahead of print]23(15):
    Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency.
    Ming-Yang Chang, Shen-Hsing Hsu, Li-Yi Ma, Li-Feng Chou, Cheng-Chieh Hung, Ya-Chung Tian, Chih-Wei Yang.
      The aberrant activation of the purinergic signaling pathway has been shown to promote cyst growth and fluid secretion in autosomal dominant polycystic kidney disease (ADPKD). Suramin is an anti-parasitic drug that has strong anti-purinergic properties. Whether suramin could have a therapeutic effect on ADPKD has not been fully investigated. We examined the effect of suramin on cyst progression in a Pkd1 microRNAs transgenic mouse model that presented stable Pkd1 knockdown and moderate disease progression. The Pkd1-deficient mice were treated with suramin (60 mg/kg) by intraperitoneal injection twice a week from postnatal days 35 to 90. Kidney-to-body weight ratios, cyst indices, and blood urea nitrogen (BUN) levels were measured. Cell proliferation and macrophage infiltration were determined by immunohistochemistry. The suramin-treated group had significantly lower renal cyst densities, cell proliferation, and macrophage infiltration compared with saline-treated controls. Suramin significantly inhibited ERK phosphorylation and the expression of Il1b, Il6, Nlrp3, Tgfb, Fn1, P2rx7, and P2ry2 mRNAs in the kidneys. However, BUN levels remained high despite the reduction in cyst growth. Furthermore, plasma cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in the suramin-treated group compared with the control group. Periodic acid-Schiff staining revealed degenerative changes and epithelial cell vacuolation in the non-cystic renal tubules, which indicated phospholipidosis following suramin treatment. These results suggest that suramin may reduce renal cyst growth and inflammation, but the associated tubular cell injuries could limit its therapeutic potential. Other purinergic receptor antagonists with less nephrotoxicity may deserve further investigation for the treatment of ADPKD.
    Keywords:  polycystic kidney disease; purinergic signaling; suramin
    DOI:  https://doi.org/10.3390/ijms23158499
  3. J Feline Med Surg. 2022 Aug 11. 1098612X221114043
    Prevalence of polycystic kidney disease in Persian and Persian-related cats in western Mexico.
    Néstor G Michel-Regalado, Miguel A Ayala-Valdovinos, Jorge Galindo-García, Theodor Duifhuis-Rivera, Abraham Virgen-Méndez.
       OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD), the most frequently diagnosed hereditary disease affecting Persian cats, is caused by a cytosine-to-adenine transversion (10063C>A) in PKD1, the gene that codes for polycystin-1. The objective of this study was to provide a preliminary estimate of the frequency of the pathogenic 10063C>A single nucleotide polymorphism (SNP) of PKD1 in Persian and Persian-related cat breeds in western Mexico.
    METHODS: Blood samples were collected from 104 cats (89 Persian, seven Persian crossbreed, five Siamese and three Himalayan cats). Genotyping was performed with our proposed PCR restriction fragment length polymorphism (RFLP) assay, as well as a previously established PCR-RFLP method for validation. The genotypes of control cats were corroborated by a commercial veterinary genetics laboratory.
    RESULTS: Our proposed PCR-RFLP assay and the validated PCR-RFLP methodology indicated that 24/104 (23.1%) cats in this study were heterozygous carriers of the 10063C>A SNP, including 23/89 Persian cats (25.8%) and 1/7 Persian crossbreed cats (14.3%). No Siamese or Himalayan cats were carriers. There were no discrepancies between the results obtained with our proposed assay and those obtained with the validation method or with commercial laboratory results.
    CONCLUSIONS AND RELEVANCE: The carrier frequency of the PKD1 10063C>A SNP in Persian and Persian-related cat breeds in western Mexico was found to be 23.1%. ADPKD frequencies among cat populations in Mexico have not been published previously. Genotyping assays can be used to facilitate the selection of breeding stocks by local breeders and veterinarians to avoid propagation of ADPKD.
    Keywords:  PCR-RFLP; PKD1; Persian; genotyping
    DOI:  https://doi.org/10.1177/1098612X221114043
  4. Curr Opin Physiol. 2020 Oct;17 278-283
    Regulation and Function of Calcium in the Cilium.
    Zhaoxia Sun.
      The cilium is a cell surface organelle with unique composition and shape. Although it has now been well appreciated as a signaling compartment for the vertebrate cell, the regulation and function of intraciliary calcium is less clear and sometimes controversial. This review focuses on publications regarding calcium in the cilium and the potential interactions between intraciliary calcium and signaling pathways mediated by cilia. Unresolved questions and future directions in the field are also discussed.
    Keywords:  calcium; cilia; left-right asymmetry; mechanosensory; polycystic kidney disease; polycystin; signaling
    DOI:  https://doi.org/10.1016/j.cophys.2020.08.019
  5. Vitam Horm. 2022 ;pii: S0083-6729(22)00047-4. [Epub ahead of print]120 345-370
    Primary cilia and PTH1R interplay in the regulation of osteogenic actions.
    Juan A Ardura, Eduardo Martín-Guerrero, Sara Heredero-Jiménez, Arancha R Gortazar.
      Primary cilia are subcellular structures specialized in sensing different stimuli in a diversity of cell types. In bone, the primary cilium is involved in mechanical sensing and transduction of signals that regulate the behavior of mesenchymal osteoprogenitors, osteoblasts and osteocytes. To perform its functions, the primary cilium modulates a plethora of molecules including those stimulated by the parathyroid hormone (PTH) receptor type I (PTH1R), a master regulator of osteogenesis. Binding of the agonists PTH or PTH-related protein (PTHrP) to the PTH1R or direct agonist-independent stimulation of the receptor activate PTH1R signaling pathways. In turn, activation of PTH1R leads to regulation of bone formation and remodeling. Herein, we describe the structure, function and molecular partners of primary cilia in the context of bone, playing special attention to those signaling pathways that are mediated directly or indirectly by PTH1R in association with primary cilia during the process of osteogenesis.
    Keywords:  Bone; Ossification; Osteogenesis; PTH receptor type I; PTH-related protein; Parathyroid hormone; Primary cilium; Signaling pathways
    DOI:  https://doi.org/10.1016/bs.vh.2022.04.001
  6. J Cell Physiol. 2022 Aug 07.
    PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion.
    Irene Tirado-Cabrera, Eduardo Martin-Guerrero, Sara Heredero-Jimenez, Juan A Ardura, Arancha R Gortázar.
      Osteocytes respond to mechanical forces controlling osteoblast and osteoclast function. Mechanical stimulation decreases osteocyte apoptosis and promotes bone formation. Primary cilia have been described as potential mechanosensors in bone cells. Certain osteogenic responses induced by fluid flow (FF) in vitro are decreased by primary cilia inhibition in MLO-Y4 osteocytes. The parathyroid hormone (PTH) receptor type 1 (PTH1R) modulates osteoblast, osteoclast, and osteocyte effects upon activation by PTH or PTH-related protein (PTHrP) in osteoblastic cells. Moreover, some actions of PTH1R seem to be triggered directly by mechanical stimulation. We hypothesize that PTH1R forms a signaling complex in the primary cilium that is essential for mechanotransduction in osteocytes and affects osteocyte-osteoclast communication. MLO-Y4 osteocytes were stimulated by FF or PTHrP (1-37). PTH1R and primary cilia signaling were abrogated using PTH1R or primary cilia specific siRNAs or inhibitors, respectively. Conditioned media obtained from mechanically- or PTHrP-stimulated MLO-Y4 cells inhibited the migration of preosteoclastic cells and osteoclast differentiation. Redistribution of PTH1R along the entire cilium was observed in mechanically stimulated MLO-Y4 osteocytic cells. Preincubation of MLO-Y4 cells with the Gli-1 antagonist, the adenylate cyclase inhibitor (SQ22536), or with the phospholipase C inhibitor (U73122), affected the migration of osteoclast precursors and osteoclastogenesis. Proteomic analysis and neutralizing experiments showed that FF and PTH1R activation control osteoclast function through the modulation of C-X-C Motif Chemokine Ligand 5 (CXCL5) and interleukin-6 (IL-6) secretion in osteocytes. These novel findings indicate that both primary cilium and PTH1R are necessary in osteocytes for proper communication with osteoclasts and show that mechanical stimulation inhibits osteoclast recruitment and differentiation through CXCL5, while PTH1R activation regulate these processes via IL-6.
    Keywords:  PTH1R; mechanotransduction; osteoclasts; osteocytes; primary cilia
    DOI:  https://doi.org/10.1002/jcp.30849
  7. Congenit Anom (Kyoto). 2022 Aug 08.
    CAROLI'S SYNDROME WITH AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE ON FETAL MRI: A CASE REPORT.
    Vanita Baberwal, Anjali Prakash, Anju Garg, Sapna Singh, Sangeeta Gupta.
      
    DOI:  https://doi.org/10.1111/cga.12490
  8. Open Biol. 2022 Aug;12(8): 220104
    A transgenic zebrafish for in vivo visualization of cilia.
    Hongyu Zhang, Zhuoya Huang, Liuliu Lv, Yuye Xin, Qian Wang, Feng Li, Lina Dong, Changxin Wu, Philip W Ingham, Zhonghua Zhao.
      Cilia are organelles for cellular signalling and motility. Mutations affecting ciliary function are also associated with cilia-related disorders (ciliopathies). The identification of cilia markers is critical for studying their function at the cellular level. Due to the lack of a conserved, short ciliary localization motif, the full-length ARL13b or 5HT6 proteins are normally used for cilia labelling. Overexpression of these genes, however, can affect the function of cilia, leading to artefacts in cilia studies. Here, we show that Nephrocystin-3 (Nphp3) is highly conserved among vertebrates and demonstrate that the N-terminal truncated peptide of zebrafish Nphp3 can be used as a gratuitous cilia-specific marker. To visualize the dynamics of cilia in vivo, we generated a stable transgenic zebrafish Tg (β-actin: nphp3N-mCherry)sx1001. The cilia in multiple cell types are efficiently labelled by the encoded fusion protein from embryonic stages to adulthood, without any developmental and physiological defects. We show that the line allows live imaging of ciliary dynamics and trafficking of cilia proteins, such as Kif7 and Smo, key regulators of the Hedgehog signalling pathway. Thus, we have generated an effective new tool for in vivo cilia studies that will help shed further light on the roles of these important organelles.
    Keywords:  Nphp3; cilia; ciliary signal peptides; live imaging; transgenic zebrafish
    DOI:  https://doi.org/10.1098/rsob.220104
  9. ACS Chem Biol. 2022 Aug 10.
    Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length.
    Young-Woo Nam, Rajasekharreddy Pala, Naglaa Salem El-Sayed, Denisse Larin-Henriquez, Farideh Amirrad, Grace Yang, Mohammad Asikur Rahman, Razan Orfali, Myles Downey, Keykavous Parang, Surya M Nauli, Miao Zhang.
      Small-conductance Ca2+-activated potassium (KCa2.x) channels are gated exclusively by intracellular Ca2+. The activation of KCa2.3 channels induces hyperpolarization, which augments Ca2+ signaling in endothelial cells. Cilia are specialized Ca2+ signaling compartments. Here, we identified compound 4 that potentiates human KCa2.3 channels selectively. The subtype selectivity of compound 4 for human KCa2.3 over rat KCa2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of KCa2.3 channels by compound 4 increased flow-induced Ca2+ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca2+ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca2+-hypersensitive KCa2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca2+-hyposensitive KCa2.3_I438N channels. Collectively, we were able to associate functions of KCa2.3 channels and cilia, two crucial components in the flow-induced Ca2+ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.
    DOI:  https://doi.org/10.1021/acschembio.2c00469
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