bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–08–06
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. CFTR and PC2, partners in the primary cilia in ADPKD.
  2. Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review.
  3. Accelerated cystogenesis by dietary protein load is dependent on, but not initiated by kidney macrophages.
  4. Aging Associates with Cilium Elongation and Dysfunction in Kidney and Pancreas.
  5. The Role of Angiotensin II Type 1 Receptor A1166C Polymorphism in Autosomal Dominant Polycystic Kidney Disease.
  6. In vivo Polycystin-1 interactome using a novel Pkd1 knock-in mouse model.
  7. Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.
  8. RPI-1 (human DCDC2) displays functional redundancy with Nephronophthisis 4 in regulating cilia biogenesis in C. elegans.
  9. Advances and challenges toward developing kidney organoids for clinical applications.
  10. Assessing motile cilia coverage and beat frequency in mammalian in vitro cell culture tissues.
  11. CiliaMiner: an integrated database for ciliopathy genes and ciliopathies.
  12. α- and β-tubulin C-terminal tails with distinct modifications are crucial for ciliary motility and assembly.
  13. Primary Ciliary Dyskinesia.
  14. IC2 participates in the cooperative activation of outer arm dynein densely attached to microtubules.
  1. Am J Physiol Cell Physiol. 2023 Jul 31.
    CFTR and PC2, partners in the primary cilia in ADPKD.
    Murali K Yanda, Cristian Ciobanu, William B Guggino, Liudmila Cebotaru.
      Defects in the primary cilium are associated with autosomal dominant polycystic kidney disease (ADPKD). We used a combination of animal models, western blotting, and confocal microscopy and discovered that CFTR and PC2 are both co-localized to the cilium in normal kidneys, with the levels of both being decreased in cystic epithelia. Cilia were longer in CFTR-null mice and in cystic cells in our ADPKD animal models. We examined septin 2, known to play a role in cilia length, to act as a diffusion barrier and to serve as an enhancer of proliferation. We found that septin 2 protein levels were upregulated and co-localized strongly with CFTR in cystic cells. Application of VX-809, the CFTR corrector, restored CFTR and PC2 toward normal in the cilia, decreased the protein levels of septin 2, and drastically reduced septin 2 co-localization with CFTR. Our data suggest that CFTR is present in the cilia and plays a role there, perhaps through its conductance of Cl-. We also postulate that septin 2 is important for localizing CFTR to the apical membrane in cystic epithelia.
    Keywords:  CFTR; Polycystin 2; cysts; polycystic kidney disease; primary cilia
    DOI:  https://doi.org/10.1152/ajpcell.00197.2023
  2. J Vasc Res. 2023 Aug 03. 1-12
    Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review.
    Melissa R Dennis, Paulo W Pires, Christopher T Banek.
      Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD.
    Keywords:  Autosomal dominant polycystic kidney disease; Autosomal recessive polycystic kidney disease; End stage renal disease; Fibrocystin; Hypertension; Polycystic kidney disease; Polycystin; Vascular dysfunction; Wire myography
    DOI:  https://doi.org/10.1159/000531647
  3. Front Med (Lausanne). 2023 ;10 1173674
    Accelerated cystogenesis by dietary protein load is dependent on, but not initiated by kidney macrophages.
    Randee Sedaka, Jifeng Huang, Shinobu Yamaguchi, Caleb Lovelady, Jung-Shan Hsu, Sejal Shinde, Malgorzata Kasztan, David K Crossman, Takamitsu Saigusa.
       Background: Disease severity of autosomal dominant polycystic kidney disease (ADPKD) is influenced by diet. Dietary protein, a recognized cyst-accelerating factor, is catabolized into amino acids (AA) and delivered to the kidney leading to renal hypertrophy. Injury-induced hypertrophic signaling in ADPKD results in increased macrophage (MФ) activation and inflammation followed by cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately stimulating MФs to promote cyst progression.
    Methods: Pkd1flox/flox mice with and without Cre (CAGG-ER) were given tamoxifen to induce global gene deletion (Pkd1KO). Pkd1KO mice were fed either a low (LP; 6%), normal (NP; 18%), or high (HP; 60%) protein diet for 1 week (early) or 6 weeks (chronic). Mice were then euthanized and tissues were used for histology, immunofluorescence and various biochemical assays. One week fed kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing.
    Results: Chronic dietary protein load in Pkd1KO mice increased kidney weight, number of kidney infiltrating and resident MФs, chemokines, cytokines and cystic index compared to LP diet fed mice. Accelerated cyst growth induced by chronic HP were attenuated by liposomal clodronate-mediated MФ depletion. Early HP diet fed Pkd1KO mice had larger cystic kidneys compared to NP or LP fed counterparts, but without increases in the number of kidney MФs, cytokines, or markers of tubular injury. RNA sequencing of tubular epithelial cells in HP compared to NP or LP diet group revealed increased expression of sodium-glutamine transporter Snat3, chloride channel Clcnka, and gluconeogenesis marker Pepck1, accompanied by increased excretion of urinary ammonia, a byproduct of glutamine. Early glutamine supplementation in Pkd1KO mice lead to kidney hypertrophy.
    Conclusion: Chronic dietary protein load-induced renal hypertrophy and accelerated cyst growth in Pkd1KO mice is dependent on both infiltrating and resident MФ recruitment and subsequent inflammatory response. Early cyst expansion by HP diet, however, is relient on increased delivery of glutamine to kidney epithelial cells, driving downstream metabolic changes prior to inflammatory provocation.
    Keywords:  glutamine; high protein; macrophage; polycystic kidney disease; renal hypertophy
    DOI:  https://doi.org/10.3389/fmed.2023.1173674
  4. Adv Biol (Weinh). 2023 Aug 03. e2300194
    Aging Associates with Cilium Elongation and Dysfunction in Kidney and Pancreas.
    Fabian Adametz, Annika Müller, Stephan Stilgenbauer, Martin D Burkhalter, Melanie Philipp.
      Cilia are best known and most studied for their manifold functions enabling proper embryonic development. Loss of cilia or dysfunction thereof results in a great variety of congenital malformations and syndromes. However, there are also cilia-driven conditions, which manifest only later in life, such as polycystic kidney disease. Even degenerative diseases in the central nervous system have recently been linked to alterations in cilia biology. Surprisingly though, there is very little knowledge regarding cilia in normally aged organisms absent any disease. Here, it is provided evidence that cilia in naturally aged mice are considerably elongated in the kidney and pancreas, respectively. Moreover, such altered cilia appear to have become dysfunctional as indicated by changes in cellular signaling.
    Keywords:  aging; cell signaling; cilia; kidney; pancreas
    DOI:  https://doi.org/10.1002/adbi.202300194
  5. Cureus. 2023 Jun;15(6): e41136
    The Role of Angiotensin II Type 1 Receptor A1166C Polymorphism in Autosomal Dominant Polycystic Kidney Disease.
    Anand Sasidharan, Bhargavi Mv, Rajkumar Mani, Sathyamurthy P.
      Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder that affects the kidney, which affects all ethnical groups worldwide, with varied clinical presentations and severity. The studies done in various parts of the world on the association between angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism and ADPKD patients have revealed inconsistent results. This study was done to assess the role of AT1R A1166C gene polymorphism in ADPKD in the South Indian population, which is the first of its kind. Methodology This is a case-control study, conducted at a tertiary care center in South India. This study was concerned with the frequency of exposure (genotype) in ADPKD patients. Peripheral blood samples from 85 unrelated ADPKD patients and 94 controls without diabetes, hypertension, or any kidney-related disease were collected. The AT1R A1166C polymorphism was compared between (i) the cases and controls, (ii) early and late stages of chronic kidney disease (CKD) (ADPKD) subjects, and (iii) ADPKD subjects with and without hypertension. Results Among the ADPKD patients, 45 (52.9%) subjects showed early stage (CKD stages 1-3), and 40 (47%) subjects showed late stage CKD (CKD stages 4 and 5). The genotype distribution of the studied 85 ADPKD patients was almost similar. No significant association was found between the genotype distribution of AT1R A1166C polymorphism in AA vs. AC (OR = 1.11; 95% CI = 0.37-3.32; p < 0.844) and A vs. C (OR = 1.11; 95% CI = 0.38-3.32; p < 0.847) between cases and controls. The genotype distributions in genetic model AA vs. AC (OR = 3.07; 95% CI = 0.56-16.8; p < 0.177) and allelic model A vs. C (OR = 2.13; 95% CI = 0.40-11.3; p < 0.364) between the early and late CKD stages of ADPKD were also not significant. No significant association of gene polymorphism was found between the non-hypertensive and hypertensive groups of ADPKD. Conclusion The results of our study suggest there is no significant association between AT1R A1166C polymorphisms and ADPKD in the South Indian population. Further, the gene polymorphism is not related to the progression of ADPKD or the presence of hypertension in ADPKD cases in South India.
    Keywords:  a1166c gene polymorphism; adpkd; angiotensin ii type 1 receptor; angiotensin receptor type 1 - at1r; at1r gene polymorphism; autosomal dominant polycystic kidney
    DOI:  https://doi.org/10.7759/cureus.41136
  6. PLoS One. 2023 ;18(8): e0289778
    In vivo Polycystin-1 interactome using a novel Pkd1 knock-in mouse model.
    Cheng-Chao Lin, Luis F Menezes, Jiahe Qiu, Elisabeth Pearson, Fang Zhou, Yu Ishimoto, D Eric Anderson, Gregory G Germino.
      PKD1 is the most commonly mutated gene causing autosomal dominant polycystic kidney disease (ADPKD). It encodes Polycystin-1 (PC1), a putative membrane protein that undergoes a set of incompletely characterized post-transcriptional cleavage steps and has been reported to localize in multiple subcellular locations, including the primary cilium and mitochondria. However, direct visualization of PC1 and detailed characterization of its binding partners remain challenging. We now report a new mouse model with HA epitopes and eGFP knocked-in frame into the endogenous mouse Pkd1 gene by CRISPR/Cas9. Using this model, we sought to visualize endogenous PC1-eGFP and performed affinity-purification mass spectrometry (AP-MS) and network analyses. We show that the modified Pkd1 allele is fully functional but the eGFP-tagged protein cannot be detected without signal amplification by secondary antibodies. Using nanobody-coupled beads and large quantities of tissue, AP-MS identified an in vivo PC1 interactome, which is enriched for mitochondrial proteins and components of metabolic pathways. These studies suggest this mouse model and interactome data will be useful to understand PC1 function, but that new methods and brighter tags will be required to track endogenous PC1.
    DOI:  https://doi.org/10.1371/journal.pone.0289778
  7. Oncogenesis. 2023 Aug 05. 12(1): 40
    Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.
    Anna S Nikonova, Alexander Y Deneka, Flaviane N Silva, Shabnam Pirestani, Rossella Tricarico, Anna A Kiseleva, Yan Zhou, Emmanuelle Nicolas, Douglas B Flieder, Sergei I Grivennikov, Erica A Golemis.
      Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1-/-;Apc-/- organoids was reduced relative to Apc-/- organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.
    DOI:  https://doi.org/10.1038/s41389-023-00486-y
  8. Turk J Biol. 2023 ;47(1): 74-83
    RPI-1 (human DCDC2) displays functional redundancy with Nephronophthisis 4 in regulating cilia biogenesis in C. elegans.
    Oktay I Kaplan.
      Projecting from most cell surfaces, cilia serve as important hubs for sensory and signaling processes and have been linked to a variety of human disorders, including Bardet-Biedl Syndrome (BBS), Meckel-Gruber Syndrome (MKS), Nephronophthisis (NPHP), and Joubert Syndrome, and these diseases are collectively known as a ciliopathy. DCDC2 is a ciliopathy protein that localizes to cilia; nevertheless, our understanding of the role of DCDC2 in cilia is still limited. We employed C. elegans to investigate the function of C. elegans RPI-1, a Caenorhabditis elegans ortholog of human DCDC2, in cilia and found that C. elegans RPI-1 localizes to the entire ciliary axoneme, but is not present in the transition zone and basal body. We generated a null mutant of C. elegans rpi-1, and our analysis with a range of fluorescence-based ciliary markers revealed that DCDC2 and nephronophthisis 4 (NPHP-4/NPHP4) display functional redundant roles in regulating cilia length and cilia positions. Taken together, our analysis discovered a novel genetic interaction between two ciliopathy disease genes (RPI-1/DCDC2 and NPHP-4/NPHP4) in C. elegans.
    Keywords:  DCDC2; NPHP4; cilia; rare diseases
    DOI:  https://doi.org/10.55730/1300-0152.2642
  9. Cell Stem Cell. 2023 Aug 03. pii: S1934-5909(23)00256-4. [Epub ahead of print]30(8): 1017-1027
    Advances and challenges toward developing kidney organoids for clinical applications.
    Ryuichi Nishinakamura.
      Kidney organoids have enabled modeling of human development and disease. While methods of generating the nephron lineage are well established, new protocols to induce another lineage, the ureteric bud/collecting duct, have been reported in the past 5 years. Many reports have described modeling of various hereditary kidney diseases, with polycystic kidney disease serving as the archetypal disease, by using patient-derived or genome-edited kidney organoids. The generation of more organotypic kidneys is also becoming feasible. In this review, I also discuss the significant challenges for more sophisticated disease modeling and for realizing the ambitious goal of generating transplantable synthetic kidneys.
    Keywords:  disease modeling; iPS cell; kidney organoid; maturation; nephron progenitor; synthetic kidney; transplantation; ureteric bud
    DOI:  https://doi.org/10.1016/j.stem.2023.07.011
  10. R Soc Open Sci. 2023 Aug;10(8): 230185
    Assessing motile cilia coverage and beat frequency in mammalian in vitro cell culture tissues.
    Ricardo Fradique, Erika Causa, Clara Delahousse, Jurij Kotar, Laetitia Pinte, Ludovic Vallier, Marta Vila-Gonzalez, Pietro Cicuta.
      Cilia density, distribution and beating frequency are important properties of airway epithelial tissues. These parameters are critical in diagnosing primary ciliary dyskinesia and examining in vitro models, including those derived from induced pluripotent stem cells. Video microscopy can be used to characterize these parameters, but most tools available at the moment are limited in the type of information they can provide, usually only describing the ciliary beat frequency of very small areas, while requiring human intervention and training for their use. We propose a novel and open-source method to fully characterize cilia beating frequency and motile cilia coverage in an automated fashion without user intervention. We demonstrate the ability to differentiate between different coverage densities, identifying even small patches of cilia in a larger field of view, and to fully characterize the cilia beating frequency of all moving areas. We also show that the method can be used to combine multiple fields of view to better describe a sample without relying on small pre-selected regions of interest. This is released with a simple graphical user interface for file handling, enabling a full analysis of individual fields of view in a few minutes on a typical personal computer.
    Keywords:  cilia; cilia beat frequency; cilia coverage; motile cilia
    DOI:  https://doi.org/10.1098/rsos.230185
  11. Database (Oxford). 2023 Jul 26. pii: baad047. [Epub ahead of print]2023
    CiliaMiner: an integrated database for ciliopathy genes and ciliopathies.
    Merve Gül Turan, Mehmet Emin Orhan, Sebiha Cevik, Oktay I Kaplan.
      Cilia are found in eukaryotic species ranging from single-celled organisms, such as Chlamydomonas reinhardtii, to humans, but not in plants. The ability to respond to repellents and/or attractants, regulate cell proliferation and differentiation and provide cellular mobility are just a few examples of how crucial cilia are to cells and organisms. Over 30 distinct rare disorders generally known as ciliopathy are caused by abnormalities or functional impairments in cilia and cilia-related compartments. Because of the complexity of ciliopathies and the rising number of ciliopathies and ciliopathy genes, a ciliopathy-oriented and up-to-date database is required. Here, we present CiliaMiner, a manually curated ciliopathy database that includes ciliopathy lists collected from articles and databases. Analysis reveals that there are 55 distinct disorders likely related to ciliopathy, with over 4000 clinical manifestations. Based on comparative symptom analysis and subcellular localization data, diseases are classified as primary, secondary or atypical ciliopathies. CiliaMiner provides easy access to all of these diseases and disease genes, as well as clinical features and gene-specific clinical features, as well as subcellular localization of each protein. Additionally, the orthologs of disease genes are also provided for mice, zebrafish, Xenopus, Drosophila, Caenorhabditis elegans and Chlamydomonas reinhardtii. CiliaMiner (https://kaplanlab.shinyapps.io/ciliaminer) aims to serve the cilia community with its comprehensive content and highly enriched interactive heatmaps, and will be continually updated. Database URL: https://kaplanlab.shinyapps.io/ciliaminer/.
    DOI:  https://doi.org/10.1093/database/baad047
  12. J Cell Sci. 2023 Jul 31. pii: jcs.261070. [Epub ahead of print]
    α- and β-tubulin C-terminal tails with distinct modifications are crucial for ciliary motility and assembly.
    Tomohiro Kubo, Yuma Tani, Haru-Aki Yanagisawa, Masahide Kikkawa, Toshiyuki Oda.
      α- and β-tubulin have an unstructured glutamate-rich region at their C-terminal tails (CTT). The function of this region in cilia/flagella is still unclear, except that glutamates in CTT act as the sites for posttranslational modifications that affect ciliary motility. A unicellular alga Chlamydomonas possesses only two a-tubulin genes and two b-tubulin genes, each pair encoding an identical protein. This simple gene organization may enable a complete replacement of the wild-type tubulin with its mutated version. Here, using CRISPR/Cas9, we generated mutants expressing tubulins with modified CTTs. We found that the mutant whose four glutamate residues in the α-tubulin CTT have been replaced by alanine almost completely lacked polyglutamylated tubulin and displayed paralyzed cilia. In contrast, the mutant lacking the glutamate-rich region of the β-tubulin CTT assembled short cilia without the central apparatus. This phenotype is similar to the mutants harboring a mutation in a subunit of katanin, whose function has been shown to depend on the b-tubulin CTT. Therefore, our study reveals distinct and important roles of α- and β-tubulin CTT in the formation and function of cilia.
    Keywords:   Chlamydomonas ; Cilia; Flagella; Polyglutamylation; Polyglycylation; Tubulin
    DOI:  https://doi.org/10.1242/jcs.261070
  13. Presse Med. 2023 Jul 27. pii: S0755-4982(23)00008-8. [Epub ahead of print] 104171
    Primary Ciliary Dyskinesia.
    Johanna Raidt, Niki Tomas Loges, Heike Olbrich, Julia Wallmeier, Petra Pennekamp, Heymut Omran.
       BACKGROUND AND OBJECTIVES: Primary ciliary dyskinesia (PCD, ORPHA:244) is a group of rare genetic disorders characterized by dysfunction of motile cilia. It is phenotypically and genetically heterogeneous, with more than 50 genes involved. Thanks to genetic, clinical, and functional characterization, immense progress has been made in the understanding and diagnosis of PCD. Nevertheless, it is underdiagnosed due to the heterogeneous phenotype and complexity of diagnosis. This review aims to help clinicians navigate this heterogeneous group of diseases. Here, we describe the broad spectrum of phenotypes associated with PCD and address pitfalls and difficult-to-interpret findings to avoid misinterpretation.
    METHOD: Review of literature CONCLUSION: PCD diagnosis is complex and requires integration of history, clinical picture, imaging, functional and structural analysis of motile cilia and, if available, genetic analysis to make a definitive diagnosis. It is critical that we continue to expand our knowledge of this group of rare disorders to improve the identification of PCD patients and to develop evidence-based therapeutic approaches.
    DOI:  https://doi.org/10.1016/j.lpm.2023.104171
  14. Cell Struct Funct. 2023 Jul 27.
    IC2 participates in the cooperative activation of outer arm dynein densely attached to microtubules.
    Yusuke Kondo, Tomoka Ogawa, Emiri Kanno, Masafumi Hirono, Takako Kato-Minoura, Ritsu Kamiya, Toshiki Yagi.
      Ciliary outer-arm dynein (OAD) consists of heavy chains (HCs), intermediate chains (ICs), and light chains (LCs), of which HCs are the motor proteins that produce force. Studies using the green alga Chlamydomonas have revealed that ICs and LCs form a complex (IC/LC tower) at the base of the OAD tail and play a crucial role in anchoring OAD to specific sites on the microtubule. In this study, we isolated a novel slow-swimming Chlamydomonas mutant deficient in the IC2 protein. This mutation, E279K, is in the third of the seven WD repeat domains. No apparent abnormality was observed in electron microscope observations of axonemes or in SDS-PAGE analyses of dynein subunits. To explore the reason for the lowered motility in this mutant, in vitro microtubule sliding experiments were performed, which revealed that the motor activity of the mutant OAD was lowered. In particular, a large difference was observed between wild type (WT) and the mutant in the microtubule sliding velocity in microtubule bundles formed with the addition of OAD: ~35.3 µm/sec (WT) and ~4.3 µm/sec (mutant). From this and other results, we propose that IC2 in an OAD interacts with the β HC of the adjacent OAD, and that an OAD-OAD interaction is important for efficient beating of cilia and flagella.Key words: cilia, axoneme, dynein heavy chain, cooperativity.
    Keywords:  axoneme; cilia; cooperativity; dynein heavy chain
    DOI:  https://doi.org/10.1247/csf.23044
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