bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–05–21
24 papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Surgical Management of Autosomal Dominant Polycystic Kidney Disease: Principles and Current Practice.
  2. Hypoxia induces polycystin-1 expression in the renal epithelium.
  3. Retraction: The Role for HNF-1β-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells.
  4. WDR31 displays functional redundancy with GTPase-activating proteins (GAPs) ELMOD and RP2 in regulating IFT complex and recruiting the BBSome to cilium.
  5. Scanning electron microscopy of human islet cilia.
  6. OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD.
  7. Massive bilateral polycystic kidneys, successful treatment with embolization and nephrectomy: A case report.
  8. Fluoroscopy and CT Guided Translumbar Tunneled Dialysis Catheter for Hemodialysis Access Failure in a Case of Autosomal Dominant Polycystic Kidney Disease.
  9. Pathophysiological Implications and Therapeutic Approach of Klotho in Chronic Kidney Disease. A Systematic Review.
  10. Dendritic cell proliferation by primary cilium in atopic dermatitis.
  11. Role of Sex Hormones in Prevalent Kidney Diseases.
  12. Eupatilin improves cilia defects in human CEP290 ciliopathy models.
  13. Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells.
  14. Skeletal ciliopathy: pathogenesis and related signaling pathways.
  15. CEP164-GLI2 association ensures the hedgehog signaling in pancreatic cancer cells.
  16. Crystal-Induced Lower GI Necrosis in a Posttransplant Recipient with Diverticular Disease.
  17. Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling.
  18. Architecture of intraflagellar transport complexes.
  19. CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability.
  20. Identification of TEKTIN1-expressing multiciliated cells during spontaneous differentiation of non-human primate embryonic stem cells.
  21. Issues in multi-organ transplantation of the liver with kidney or heart in polycystic liver-kidney disease or congenital heart disease: Current practices and immunological aspects.
  22. Evidence for Kidney Volume as a Measure of ADPKD Severity "Marches On" in the OVERTURE Study.
  23. Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases.
  24. Rab8, Rab11, and Rab35 coordinate lumen and cilia formation during zebrafish left-right organizer development.
  1. JNMA J Nepal Med Assoc. 2023 May 01. 61(261): 485-491
    Surgical Management of Autosomal Dominant Polycystic Kidney Disease: Principles and Current Practice.
    Badri Man Shrestha.
      Autosomal dominant polycystic kidney disease is the third most common cause of renal failure with no definitive treatment available that can directly target the development and growth of the cysts. Endeavours are being made to retard the growth of the cysts and preservation of renal function through medical treatment. However, 50% of the autosomal dominant polycystic kidney disease-affected persons develop complications and end-stage renal disease by the age of fifty-five and need surgical intervention for the management of complications, creation of dialysis access and renal transplantation. This review highlights the principles and current practice pertinent to the surgical management of autosomal dominant polycystic kidney disease.
    Keywords: polycystic kidney disease; nephrectomy; transplantation.
    DOI:  https://doi.org/10.31729/jnma.8159
  2. R Soc Open Sci. 2023 May;10(5): 220992
    Hypoxia induces polycystin-1 expression in the renal epithelium.
    Steffen Grampp, Andre Kraus, Kathrin Skoczynski, Mario Schiffer, René Krüger, Stephanie Naas, Johannes Schödel, Bjoern Buchholz.
      Mutations in polycystin-1 which is encoded by the PKD1 gene are the main causes for the development of autosomal dominant polycystic kidney disease. However, only little is known about the physiological function of polycystin-1 and even less about the regulation of its expression. Here, we show that expression of PKD1 is induced by hypoxia and compounds that stabilize the hypoxia-inducible transcription factor (HIF) 1α in primary human tubular epithelial cells. Knockdown of HIF subunits confirms HIF-1α-dependent regulation of polycystin-1 expression. Furthermore, HIF ChIP-seq reveals that HIF interacts with a regulatory DNA element within the PKD1 gene in renal tubule-derived cells. HIF-dependent expression of polycystin-1 can also be demonstrated in vivo in kidneys of mice treated with substances that stabilize HIF. Polycystin-1 and HIF-1α have been shown to promote epithelial branching during kidney development. In line with these findings, we show that expression of polycystin-1 within mouse embryonic ureteric bud branches is regulated by HIF. Our finding links expression of one of the main regulators of accurate renal development with the hypoxia signalling pathway and provides additional insight into the pathophysiology of polycystic kidney disease.
    Keywords:  PKD1; hypoxia; hypoxia-inducible factor; kidney development; polycystic kidney disease; transcription regulation
    DOI:  https://doi.org/10.1098/rsos.220992
  3. PLoS One. 2023 ;18(5): e0286174
    Retraction: The Role for HNF-1β-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells.
    PLOS ONE Editors
      
    DOI:  https://doi.org/10.1371/journal.pone.0286174
  4. Life Sci Alliance. 2023 Aug;pii: e202201844. [Epub ahead of print]6(8):
    WDR31 displays functional redundancy with GTPase-activating proteins (GAPs) ELMOD and RP2 in regulating IFT complex and recruiting the BBSome to cilium.
    Sebiha Cevik, Xiaoyu Peng, Tina Beyer, Mustafa S Pir, Ferhan Yenisert, Franziska Woerz, Felix Hoffmann, Betul Altunkaynak, Betul Pir, Karsten Boldt, Asli Karaman, Miray Cakiroglu, S Sadik Oner, Ying Cao, Marius Ueffing, Oktay I Kaplan.
      The correct intraflagellar transport (IFT) assembly at the ciliary base and the IFT turnaround at the ciliary tip are key for the IFT to perform its function, but we still have poor understanding about how these processes are regulated. Here, we identify WDR31 as a new ciliary protein, and analysis from zebrafish and Caenorhabditis elegans reveals the role of WDR31 in regulating the cilia morphology. We find that loss of WDR-31 together with RP-2 and ELMD-1 (the sole ortholog ELMOD1-3) results in ciliary accumulations of IFT Complex B components and KIF17 kinesin, with fewer IFT/BBSome particles traveling along cilia in both anterograde and retrograde directions, suggesting that the IFT/BBSome entry into the cilia and exit from the cilia are impacted. Furthermore, anterograde IFT in the middle segment travels at increased speed in wdr-31;rpi-2;elmd-1 Remarkably, a non-ciliary protein leaks into the cilia of wdr-31;rpi-2;elmd-1, possibly because of IFT defects. This work reveals WDR31-RP-2-ELMD-1 as IFT and BBSome trafficking regulators.
    DOI:  https://doi.org/10.26508/lsa.202201844
  5. Proc Natl Acad Sci U S A. 2023 May 30. 120(22): e2302624120
    Scanning electron microscopy of human islet cilia.
    Alexander J Polino, Sanja Sviben, Isabella Melena, David W Piston, Jing W Hughes.
      Human islet primary cilia are vital glucose-regulating organelles whose structure remains uncharacterized. Scanning electron microscopy (SEM) is a useful technique for studying the surface morphology of membrane projections like cilia, but conventional sample preparation does not reveal the submembrane axonemal structure, which holds key implications for ciliary function. To overcome this challenge, we combined SEM with membrane-extraction techniques to examine primary cilia in native human islets. Our data show well-preserved cilia subdomains which demonstrate both expected and unexpected ultrastructural motifs. Morphometric features were quantified when possible, including axonemal length and diameter, microtubule conformations, and chirality. We further describe a ciliary ring, a structure that may be a specialization in human islets. Key findings are correlated with fluorescence microscopy and interpreted in the context of cilia function as a cellular sensor and communications locus in pancreatic islets.
    Keywords:  human islets; primary cilia; scanning electron microscopy
    DOI:  https://doi.org/10.1073/pnas.2302624120
  6. Kidney Int Rep. 2023 May;8(5): 989-1001
    OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD.
    Ronald D Perrone, Dorothee Oberdhan, John Ouyang, Daniel G Bichet, Klemens Budde, Arlene B Chapman, Berenice Y Gitomer, Shigeo Horie, Albert C M Ong, Vicente E Torres, A Neil Turner, Holly Krasa.
       Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD.
    Methods: This prospective study enrolled a large international population (N = 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity.
    Results: Most subjects (84.4%) completed ≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up.
    Conclusion: Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function.
    Keywords:  autosomal dominant polycystic kidney disease; cohort; disease progression; natural history; observational; patient-reported outcomes
    DOI:  https://doi.org/10.1016/j.ekir.2023.02.1073
  7. Urol Case Rep. 2023 May;48 102422
    Massive bilateral polycystic kidneys, successful treatment with embolization and nephrectomy: A case report.
    Ibrahim Boukhannous, Anouar El Moudane, Elhadi Irsani, Mohamed Irzi, Abdelghani Ouraghi, Ali Barki.
      Polycystic kidney disease (PKD) is a genetic disorder characterized by the formation of multiple cysts in the kidneys. We present a case of a 47-year-old male with PKD on dialysis who underwent bilateral renal artery embolization followed by bilateral nephrectomy via a median incision. The specimen weight was 5 kg for the left kidney and 8 kg for the right one. Renal artery embolization can be a useful tool in managing polycystic kidney disease in cases where nephrectomy is indicated. This case highlights the importance of timely intervention and the role of minimally invasive techniques in managing this rare condition.
    Keywords:  Bilateral nephrectomy; Giant polycystic kidney; Renal artery embolization
    DOI:  https://doi.org/10.1016/j.eucr.2023.102422
  8. Indian J Nephrol. 2023 Jan-Feb;33(1):33(1): 70-74
    Fluoroscopy and CT Guided Translumbar Tunneled Dialysis Catheter for Hemodialysis Access Failure in a Case of Autosomal Dominant Polycystic Kidney Disease.
    Krantikumar Rathod, Punit Mahajan, Dhaval Thakkar, Tukaram Jamale, Hemant Deshmukh.
      Vascular access in hemodialysis is essential to end-stage renal disease (ESRD) patients' survival. Unfortunately, even after years of recent advances, a significant number of patients may develop multi-access failure for many reasons. In this situation, arterial-venous fistula (AVF) or catheters placement in traditional vascular sites (jugular, femoral, or subclavian) are not feasible. In this scenario, translumbar tunneled dialysis catheters (TLDCs) may be a salvage option. The use of central venous catheters (CVC) is associated with an increased incidence of venous stenosis that can progressively limit future vascular access routes. The common femoral vein can be used for temporary access in patients in whom traditional approaches for permanent central venous access may not be feasible because of either chronically occluded or not accessible vasculature; however, this location is not preferred for long-term venous access because of the high rate of catheter related blood stream infections (CRBSI). In these patients, a direct translumbar approach to the inferior vena cava is a lifesaving alternative. This approach has been described by several authors as a bail-out option. Fluoroscopy-guided access via a translumbar approach into the inferior vena cava bares the risk of hollow-organ perforation or severe bleeding from the inferior vena cava or even the aorta. To minimize the risk of complications caused by a translumbar central venous access, we hereby present a hybrid approach with CT-guided translumbar access of the inferior vena cava followed by a conventional implantation of the permanent central venous catheter. CT scan-guided access of IVC that further helps in our case as patient has large bulky kidneys secondary to autosomal dominant polycystic kidney disease.
    Keywords:  Hemodialysis; translumbar; tunneled dialysis catheter
    DOI:  https://doi.org/10.4103/ijn.ijn_429_21
  9. Lab Invest. 2023 May 17. pii: S0023-6837(23)00121-6. [Epub ahead of print] 100178
    Pathophysiological Implications and Therapeutic Approach of Klotho in Chronic Kidney Disease. A Systematic Review.
    Rafael Fernandez Castillo.
      The Klotho protein, known as an anti-aging protein, is expressed mainly in the kidney, and kidney disorders may contribute to disrupted expression of renal Klotho. The purpose of this systematic review was to determine if there are biological and nutraceutical therapies that increase the expression of Klotho and can help prevent complications associated with CKD. A systematic literature review was carried out through the consultation of PubMed, Scopus, and Web of Science. Records between the years 2012 and 2022 in Spanish and English were selected. Cross-sectional or prevalence and analytical studies were included that evaluated the effects of Klotho therapy. A total of 22 studies were identified after the critical reading of these selected studies. Three investigated the association between Klotho and growth factors; two evaluated the relationship between the concentration of Klotho and the type of fibrosis; three focused on the relationship between vascular calcifications and vitamin D; two assessed the relationship between Klotho and bicarbonate; two investigated the relationship between proteinuria and Klotho; one demonstrated the applicability of synthetic antibodies as a support for Klotho deficiency; one investigated Klotho hypermethylation as a renal biomarker; two investigated the relationship between proteinuria and Klotho; four linked Klotho as an early marker of CKD; one investigated Klotho levels in patients with autosomal dominant polycystic kidney disease. In conclusion, no study has addressed the comparison of these therapies in the context of their use with nutraceutical agents that raise the expression of Klotho.
    Keywords:  Chronic kidney disease; Vitamin D; nutraceutical agents; vascular calcification; α-Klotho
    DOI:  https://doi.org/10.1016/j.labinv.2023.100178
  10. Front Mol Biosci. 2023 ;10 1149828
    Dendritic cell proliferation by primary cilium in atopic dermatitis.
    Manami Toriyama, Defri Rizaldy, Motoki Nakamura, Yukiko Atsumi, Michinori Toriyama, Fumitaka Fujita, Fumihiro Okada, Akimichi Morita, Hiroshi Itoh, Ken J Ishii.
      Introduction: Atopic dermatitis (AD) is a common allergic eczema that affects up to 10% of adults in developed countries. Immune cells in the epidermis, namely, Langerhans cells (LCs), contribute to the pathogenesis of AD, although their exact role(s) in disease remain unclear. Methods: We performed immunostaining on human skin and peripheral blood mononuclear cells (PBMCs) and visualized primary cilium. Result and discussion: We show that human dendritic cells (DCs) and LCs have a previously unknown primary cilium-like structure. The primary cilium was assembled during DC proliferation in response to the Th2 cytokine GM-CSF, and its formation was halted by DC maturation agents. This suggests that the role of primary cilium is to transduce proliferation signaling. The platelet-derived growth factor receptor alpha (PDGFRα) pathway, which is known for transducing proliferation signals in the primary cilium, promoted DC proliferation in a manner dependent on the intraflagellar transport (IFT) system. We also examined the epidermal samples from AD patients, and observed aberrantly ciliated LCs and keratinocytes in immature and proliferating states. Our results identify a potential relationship between the primary cilium and allergic skin barrier disorders, and suggest that targeting the primary cilium may contribute to treating AD.
    Keywords:  atopic dermatitis; dendritic cell; keratinocytes; langerhans cell; pdgf signaling; primary cilium
    DOI:  https://doi.org/10.3389/fmolb.2023.1149828
  11. Int J Mol Sci. 2023 May 04. pii: 8244. [Epub ahead of print]24(9):
    Role of Sex Hormones in Prevalent Kidney Diseases.
    Carolina Conte, Giulia Antonelli, Maria Elena Melica, Mirko Tarocchi, Paola Romagnani, Anna Julie Peired.
      Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD is more frequent in females, males have a higher risk to progress to end-stage kidney disease. In recent years, numerous studies have highlighted the role of sex hormones in the health and diseases of several organs, including the kidney. In this review, we present a clinical overview of the sex-differences in CKD and a selection of prominent kidney diseases causing CKD: lupus nephritis, diabetic kidney disease, IgA nephropathy, and autosomal dominant polycystic kidney disease. We report clinical and experimental findings on the role of sex hormones in the development of the disease and its progression to end-stage kidney disease.
    Keywords:  IgA nephropathy; animal models; autosomal dominant polycystic kidney disease; chronic kidney disease; diabetic kidney disease; end-stage kidney disease; lupus nephritis; sex hormones
    DOI:  https://doi.org/10.3390/ijms24098244
  12. bioRxiv. 2023 Apr 12. pii: 2023.04.12.536565. [Epub ahead of print]
    Eupatilin improves cilia defects in human CEP290 ciliopathy models.
    J C Corral-Serrano, P E Sladen, D Ottaviani, F O Rezek, K Jovanovic, D Athanasiou, J van der Spuy, B C Mansfield, M E Cheetham.
      The photoreceptor outer segment is a highly specialized primary cilium essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290 , there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290 -related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids, by modulating the expression of rhodopsin, and by targeting cilia and synaptic plasticity pathways. This work sheds light into the mechanism of action of eupatilin, and supports its potential as a variant-independent approach for CEP290 -associated ciliopathies.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2023.04.12.536565
  13. Cells. 2023 05 03. pii: 1307. [Epub ahead of print]12(9):
    Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells.
    Gary S L Peh, Francisco Bandeira, Dawn Neo, Khadijah Adnan, Yossa Hartono, Hon Shing Ong, Sacha Naso, Anandalakshmi Venkatraman, José A P Gomes, Viridiana Kocaba, Jodhbir S Mehta.
      (1) Rho-associated coiled-coil protein kinase (ROCK) signaling cascade impacts a wide array of cellular events. For cellular therapeutics, scalable expansion of primary human corneal endothelial cells (CECs) is crucial, and the inhibition of ROCK signaling using a well characterized ROCK inhibitor (ROCKi) Y-27632 had been shown to enhance overall endothelial cell yield. (2) In this study, we compared several classes of ROCK inhibitors to both ROCK-I and ROCK-II, using in silico binding simulation. We then evaluated nine ROCK inhibitors for their effects on primary CECs, before narrowing it down to the two most efficacious compounds-AR-13324 (Netarsudil) and its active metabolite, AR-13503-and assessed their impact on cellular proliferation in vitro. Finally, we evaluated the use of AR-13324 on the regenerative capacity of donor cornea with an ex vivo corneal wound closure model. Donor-matched control groups supplemented with Y-27632 were used for comparative analyses. (3) Our in silico simulation revealed that most of the compounds had stronger binding strength than Y-27632. Most of the nine ROCK inhibitors assessed worked within the concentrations of between 100 nM to 30 µM, with comparable adherence to that of Y-27632. Of note, both AR-13324 and AR-13503 showed better cellular adherence when compared to Y-27632. Similarly, the proliferation rates of CECs exposed to AR-13324 were comparable to those of Y-27632. Interestingly, CECs expanded in a medium supplemented with AR-13503 were significantly more proliferative in (i) untreated vs. AR-13503 (1 μM; * p < 0.05); (ii) untreated vs. AR-13503 (10 μM; *** p < 0.001); (iii) Y-27632 vs. AR-13503 (10 μM; ** p < 0.005); (iv) AR-13324 (1 μM) vs. AR-13503 (10 μM; ** p < 0.005); and (v) AR-13324 (0.1 μM) vs. AR-13503 (10 μM; * p < 0.05). Lastly, an ex vivo corneal wound healing study showed a comparable wound healing rate for the final healed area in corneas exposed to Y-27632 or AR-13324. (4) In conclusion, we were able to demonstrate that various classes of ROCKi compounds other than Y-27632 were able to exert positive effects on primary CECs, and systematic donor-match controlled comparisons revealed that the FDA-approved ROCK inhibitor, AR-13324, is a potential candidate for cellular therapeutics or as an adjunct drug in regenerative treatment for corneal endothelial diseases in humans.
    Keywords:  Rho-associated coiled-coil protein kinase; cell injection; cell therapy; cornea; corneal endothelium; corneal transplantation; ophthalmology; primary human corneal endothelial cells; regenerative medicine
    DOI:  https://doi.org/10.3390/cells12091307
  14. Mol Cell Biochem. 2023 May 15.
    Skeletal ciliopathy: pathogenesis and related signaling pathways.
    Bowen Lai, Heng Jiang, Yuan Gao, Xuhui Zhou.
      Cilia are tiny organelles with conserved structures and components in eukaryotic cells. Ciliopathy is a set of diseases resulting from cilium dysfunction classified into first-order and second-order ciliopathy. With the advancement of clinical diagnosis and radiography, numerous skeletal phenotypes, including polydactyly, short limbs, short ribs, scoliosis, a narrow thorax, and numerous anomalies in bone and cartilage, have been discovered in ciliopathies. Mutation in genes encoding cilia core components or other cilia-related molecules have been found in skeletal ciliopathies. Meanwhile, various signaling pathways associated with cilia and skeleton development have been deemed to be significant for the occurrence and progression of diseases. Herein, we review the structure and key components of the cilium and summarize several skeletal ciliopathies with their presumable pathology. We also emphasize the signaling pathways involved in skeletal ciliopathies, which may assist in developing potential therapies for these diseases.
    Keywords:  Bone disease; Cilia; Ciliopathy; Hedgehog; Signaling; Skeletal ciliopathy
    DOI:  https://doi.org/10.1007/s11010-023-04765-5
  15. Biochem Biophys Res Commun. 2023 May 10. pii: S0006-291X(23)00593-4. [Epub ahead of print]666 179-185
    CEP164-GLI2 association ensures the hedgehog signaling in pancreatic cancer cells.
    Toshihiko Fushimi, Tetsuo Kobayashi, Hiroshi Itoh.
      Hedgehog (Hh) signaling is involved in multiple biological events including development and cancers. It is processed through primary cilia, which are assembled from the mother centriole in most mammalian cells. Pancreatic ductal adenocarcinoma (PDAC) cells generally lose their primary cilia; thus, the Hh signaling pathway is postulated to be independent of the organelle in PDAC. We previously reported that the mother centriole-specific protein, centrosomal protein 164 (CEP164), is required for centriolar localization of the GLI2 transcription factor in Hh signaling and for suppressing the expression of Hh-target genes. In this study, we demonstrated the physical interaction between CEP164 and GLI2, and delineated their binding modes at the mother centriole. The ectopically expressed GLI2-binding region of CEP164 reduced the centriolar GLI2 localization and enhanced the expression of Hh-target genes in PDAC cells. Furthermore, similar phenotypes were observed in PDAC cells lacking primary cilia. These results suggest that the CEP164-GLI2 association at the mother centriole is responsible for controlling Hh signaling, independent of primary cilia in PDAC cells.
    Keywords:  CEP164; Centriole; GLI2; Hedgehog signaling; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2023.05.031
  16. Indian J Nephrol. 2023 Jan-Feb;33(1):33(1): 54-56
    Crystal-Induced Lower GI Necrosis in a Posttransplant Recipient with Diverticular Disease.
    Maithrayie Kumaresan, R S Arun, Aditi Damle, Rajeevalochana Parthasarathy, Milly Matthew, Gerogi Abraham.
      We report the case of a 67-year-old male kidney transplant recipient for 12 years with sodium polystyrene sulfonate crystal-induced ileocecal colitis. He had adult polycystic kidney disease with associated colonic diverticular disease. Here, we describe how a potentially fatal complication of colonic perforation was averted with appropriate investigations and management.
    Keywords:  Hyperkalemia; ileocecal colitis; sodium polystyrene sulfonate crystals
    DOI:  https://doi.org/10.4103/ijn.IJN_564_20
  17. Cell Insight. 2022 Oct;1(5): 100055
    Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling.
    Gongsheng Yuan, Shu-Ting Yang, Shuying Yang.
      Angiogenesis is the formation of new capillaries that plays an essential role in the pathogenesis of inflammatory arthritis. However, the cellular and molecular mechanisms remain unclear. Here, we provide the first evidence that regulator of G-protein signaling 12 (RGS12) promotes angiogenesis in inflammatory arthritis through governing ciliogenesis and cilia elongation in endothelial cells. The knockout of RGS12 inhibits the development of inflammatory arthritis with the reduction in clinical score, paw swelling, and angiogenesis. Mechanistically, RGS12 overexpression (OE) in endothelial cells increases cilia number and length, and thereby promotes cell migration and tube-like structure formation. The knockout of cilia marker protein Intraflagellar transport (IFT) 80 blocked the increase in cilia number and length caused by RGS12 OE. Moreover, the results from LC/MS and IP analysis showed that RGS12 is associated with cilia-related protein MYC binding protein 2 (MYCBP2), which enhances the phosphorylation of MYCBP2 to promote ciliogenesis in endothelial cells. These findings demonstrate that upregulation of RGS12 by inflammation enhances angiogenesis by promoting cilia formation and elongation via activation of MYCBP2 signaling during inflammatory arthritis pathogenesis.
    DOI:  https://doi.org/10.1016/j.cellin.2022.100055
  18. Nat Struct Mol Biol. 2023 05;30(5): 570-573
    Architecture of intraflagellar transport complexes.
    Takashi Ishikawa.
      
    DOI:  https://doi.org/10.1038/s41594-023-00986-w
  19. Dev Biol. 2023 May 10. pii: S0012-1606(23)00067-2. [Epub ahead of print]
    CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability.
    E Deniz, M Pasha, M E Guerra, S Viviano, W Ji, M Konstantino, L Jeffries, S A Lakhani, L Medne, C Skraban, I Krantz, M K Khokha.
      Congenital heart disease (CHD) is the most common and lethal birth defect, affecting 1.3 million individuals worldwide. During early embryogenesis, errors in Left-Right (LR) patterning called Heterotaxy (Htx) can lead to severe CHD. Many of the genetic underpinnings of Htx/CHD remain unknown. In analyzing a family with Htx/CHD using whole-exome sequencing, we identified a homozygous recessive missense mutation in CFAP45 in two affected siblings. CFAP45 belongs to the coiled-coil domain-containing protein family, and its role in development is emerging. When we depleted Cfap45 in frog embryos, we detected abnormalities in cardiac looping and global markers of LR patterning, recapitulating the patient's heterotaxy phenotype. In vertebrates, laterality is broken at the Left-Right Organizer (LRO) by motile monocilia that generate leftward fluid flow. When we analyzed the LRO in embryos depleted of Cfap45, we discovered "bulges" within the cilia of these monociliated cells. In addition, epidermal multiciliated cells lost cilia with Cfap45 depletion. Via live confocal imaging, we found that Cfap45 localizes in a punctate but static position within the ciliary axoneme, and depletion leads to loss of cilia stability and eventual detachment from the cell's apical surface. This work demonstrates that in Xenopus, Cfap45 is required to sustain cilia stability in multiciliated and monociliated cells, providing a plausible mechanism for its role in heterotaxy and congenital heart disease.
    Keywords:  CFAP45; Cilia; Congenital heart disease; Heterotaxy; Xenopus
    DOI:  https://doi.org/10.1016/j.ydbio.2023.04.006
  20. Genes Cells. 2023 Apr 26.
    Identification of TEKTIN1-expressing multiciliated cells during spontaneous differentiation of non-human primate embryonic stem cells.
    Tomomi Nishie, Yoshio Ohta, Emi Shirai, Shogo Higaki, Nobuhiro Shimozawa, Keishi Narita, Kotoku Kawaguchi, Hideyuki Tanaka, Chika Mori, Taiga Tanaka, Masumi Hirabayashi, Hirofumi Suemori, Akira Kurisaki, Ikuo Tooyama, Shinji Asano, Sén Takeda, Tatsuyuki Takada.
      Tektins are a group of microtubule-stabilizing proteins necessary for cilia and flagella assembly. TEKTIN1 (TEKT1) is used as a sperm marker for monitoring germ cell differentiation in embryonic stem (ES) and induced pluripotent stem (iPS) cells. Although upregulation of TEKT1 has been reported during spontaneous differentiation of ES and iPS cells, it is unclear which cells express TEKT1. To identify TEKT1-expressing cells, we established an ES cell line derived from cynomolgus monkeys (Macaca fascicularis), which expresses Venus controlled by the TEKT1 promoter. Venus expression was detected at 5 weeks of differentiation on the surface of the embryoid body (EB), and it gradually increased with the concomitant formation of a leash-like structure at the EB periphery. Motile cilia were observed on the surface of the Venus-positive leash-like structure after 8 weeks of differentiation. The expression of cilia markers as well as TEKT1-5 and 9 + 2 microtubule structures, which are characteristic of motile cilia, were detected in Venus-positive cells. These results demonstrated that TEKT1-expressing cells are multiciliated epithelial-like cells that form a leash-like structure during the spontaneous differentiation of ES and iPS cells. These findings will provide a new research strategy for studying cilia biology, including ciliogenesis and ciliopathies.
    Keywords:  TEKTIN; cilia; embryonic stem cell; flagella; induced pluripotent stem cell; non-human primate
    DOI:  https://doi.org/10.1111/gtc.13031
  21. J Hepatol. 2023 Jun;pii: S0168-8278(23)00100-9. [Epub ahead of print]78(6): 1157-1168
    Issues in multi-organ transplantation of the liver with kidney or heart in polycystic liver-kidney disease or congenital heart disease: Current practices and immunological aspects.
    Timucin Taner, Moira B Hilscher, Christopher R Broda, Joost P H Drenth.
      Solid organ transplantation has become an integral part of the management of patients with end-stage diseases of the kidney, liver, heart and lungs. Most procedures occur in isolation, but multi-organ transplantation of the liver with either the kidney or heart has become an option. As more patients with congenital heart disease and cardiac cirrhosis survive into adulthood, particularly after the Fontan procedure, liver transplant teams are expected to face questions regarding multi-organ (heart-liver) transplantation. Similarly, patients with polycystic kidneys and livers may be managed by multi-organ transplantation. Herein, we review the indications and outcomes of simultaneous liver-kidney transplantation for polycystic liver-kidney disease, and discuss the indications, timing and procedural aspects of combined heart-liver transplantation. We also summarise the evidence for, and potential mechanisms underlying, the immunoprotective impact of liver allografts on the simultaneously transplanted organs.
    Keywords:  Fontan circulation; Fontan-associated liver disease; congenital heart disease; heart-liver transplant; immunomodulation; liver-kidney transplant; polycystic kidney disease; polycystic liver disease
    DOI:  https://doi.org/10.1016/j.jhep.2023.02.012
  22. Kidney Int Rep. 2023 May;8(5): 951-953
    Evidence for Kidney Volume as a Measure of ADPKD Severity "Marches On" in the OVERTURE Study.
    Matthew B Lanktree.
      
    DOI:  https://doi.org/10.1016/j.ekir.2023.03.002
  23. iScience. 2023 May 19. 26(5): 106652
    Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases.
    Toshiki Takahashi, Jun Shirai, Miyo Matsuda, Sae Nakanaga, Shin Matsushita, Kei Wakita, Mizuki Hayashishita, Rigel Suzuki, Aya Noguchi, Naoto Yokota, Hiroyuki Kawahara.
      The small GTPase Rab8 plays a vital role in the vesicular trafficking of cargo proteins from the trans-Golgi network to target membranes. Upon reaching its target destination, Rab8 is released from the vesicular membrane into the cytoplasm via guanosine triphosphate (GTP) hydrolysis. The fate of GDP-bound Rab8 released from the destination membranes, however, has not been investigated adequately. In this study, we found that GDP-bound Rab8 subfamily proteins are targeted for immediate degradation, and the pre-emptive quality control machinery is responsible for eliminating these proteins in a nucleotide-specific manner. We provide evidence that components of this quality control machinery have a critical role in vesicular trafficking events, including the formation of primary cilia, a process regulated by the Rab8 subfamily. These results suggest that the protein degradation machinery plays a critical role in the integrity of membrane trafficking by limiting the excessive accumulation of GDP-bound Rab8 subfamily proteins.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106652
  24. PLoS Genet. 2023 May 15. 19(5): e1010765
    Rab8, Rab11, and Rab35 coordinate lumen and cilia formation during zebrafish left-right organizer development.
    Abrar A Aljiboury, Eric Ingram, Nikhila Krishnan, Favour Ononiwu, Debadrita Pal, Julie Manikas, Christopher Taveras, Nicole A Hall, Jonah Da Silva, Judy Freshour, Heidi Hehnly.
      An essential process during Danio rerio's left-right organizer (Kupffer's Vesicle, KV) formation is the formation of a motile cilium by developing KV cells which extends into the KV lumen. Beating of motile cilia within the KV lumen directs fluid flow to establish the embryo's left-right axis. However, the timepoint at which KV cells start to form cilia and how cilia formation is coordinated with KV lumen formation have not been examined. We identified that nascent KV cells form cilia at their centrosomes at random intracellular positions that then move towards a forming apical membrane containing cystic fibrosis transmembrane conductance regulator (CFTR). Using optogenetic clustering approaches, we found that Rab35 positive membranes recruit Rab11 to modulate CFTR delivery to the apical membrane, which is required for lumen opening, and subsequent cilia extension into the lumen. Once the intracellular cilia reach the CFTR positive apical membrane, Arl13b-positive cilia extend and elongate in a Rab8 dependent manner into the forming lumen once the lumen reaches an area of 300 μm2. These studies demonstrate the need to acutely coordinate Rab8, Rab11, and Rab35-mediated membrane trafficking events to ensure appropriate timing in lumen and cilia formation during KV development.
    DOI:  https://doi.org/10.1371/journal.pgen.1010765
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