bims-bicyki 2022-08-21 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–08–21
eleven papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

13-year Imaging changes for a patient with autosomal dominant polycystic kidney disease.
PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.
The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease.
Intraflagellar transport 1 20 cilia-dependent and cilia-independent signaling pathways in cell development and tissue homeostasis.
Evaluation of galectin-3 and intestinal fatty acid binding protein as serum biomarkers in autosomal recessive polycystic kidney disease.
Purification and Immunostaining of Mouse Ependymal Ciliary Shafts.
DYF-5/MAK-dependent phosphorylation promotes ciliary tubulin unloading.
Renal Dynamic Scintigraphy as a Sensitive Tool for Detecting Small Volume Urinoma Following Live-Related Renal Transplant.
Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.
Cilia regulate meiotic recombination in zebrafish.
Romosozumab successfully regulated progressive osteoporosis in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis.

Am J Gastroenterol. 2022 Aug 12.

13-year Imaging changes for a patient with autosomal dominant polycystic kidney disease.

Jun Tie, Xulong Yuan.

DOI: https://doi.org/10.14309/ajg.0000000000001934
Nat Commun. 2022 Aug 15. 13(1): 4765

PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression.

Ronak Lakhia, Harini Ramalingam, Chun-Mien Chang, Patricia Cobo-Stark, Laurence Biggers, Andrea Flaten, Jesus Alvarez, Tania Valencia, Darren P Wallace, Edmund C Lee, Vishal Patel.

Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3'-UTR miR-17 binding element. Eliminating this motif (Pkd1∆17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3'-UTR miR-17 motif, and Pkd2∆17-induced Polycystin-2 derepression retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1∆17 or PKD2∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3'-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.

DOI: https://doi.org/10.1038/s41467-022-32543-2
Am J Physiol Renal Physiol. 2022 Aug 18.

The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease.

Shirin V Sundar, Julie Xia Zhou, Brenda S Magenheimer, Gail A Reif, Darren P Wallace, Gunda I Georg, Sudhakar R Jakkaraj, Joseph S Tash, Alan S L Yu, Xiaogang Li, James P Calvet.

  Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl- secretion. We tested the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl--mediated short-circuit currents in human ADPKD cells and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and decreased hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of Hsp90, and it decreased the levels of the CFTR Cl- channel protein. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox: Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl- secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

Keywords:  ADPKD; CFTR; Hsp90

DOI:  https://doi.org/10.1152/ajprenal.00095.2022
Int J Dev Biol. 2022 Aug 17.

Intraflagellar transport 1 20 cilia-dependent and cilia-independent signaling pathways in cell development and tissue homeostasis.

Fuchang Jin, Ming-Hui Zhou, Jingjing Chen, Yi Lin, Qiwei Zhang, Qiuxian Xu, Changchun Zhang, Zhen-Gang Zhang.

Intraflagellar transport (IFT) is an essential condition for the ciliogenesis. The primary cilia protrude like antennae and act as chemical or mechanical sensory organelles that coordinate specific receptor localization and signal transduction. IFT20 is the smallest molecule in IFT complex B, which is located in both the cilia and the Golgi complex. Recent studies shown that IFT20 is a key molecule in multiple signaling pathways. Importantly, in the function of IFT20 signal transduction is not restricted to cilia, but is also involved in non-ciliary functions. Here we summarize current knowledge regarding IFT20-mediated signaling pathways and their relationship with cell development and tissue homeostasis, probe into the cilia-dependent and cilia-independent mechanisms of IFT20 coordinated signaling pathways and how possible crosstalk between the mechanisms. This review provides a comprehensive perspective on IFT20 coordinates signaling mechanisms in cell development and tissue homeostasis.

DOI: https://doi.org/10.1387/ijdb.220072fj
J Nephrol. 2022 Aug 18.

Evaluation of galectin-3 and intestinal fatty acid binding protein as serum biomarkers in autosomal recessive polycystic kidney disease.

Lindsay T Fleischer, Lance Ballester, Mohini Dutt, Kathryn Howarth, Laura Poznick, Kassa Darge, Susan L Furth, Erum A Hartung.

   BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) causes fibrocystic kidney disease, congenital hepatic fibrosis, and portal hypertension. Serum galectin-3 (Gal-3) and intestinal fatty acid binding protein (I-FABP) are potential biomarkers of kidney fibrosis and portal hypertension, respectively. We examined whether serum Gal-3 associates with kidney disease severity and serum I-FABP associates with liver disease severity in ARPKD.
METHODS: Cross-sectional study of 29 participants with ARPKD (0.2-21 years old) and presence of native kidneys (Gal-3 analyses, n = 18) and/or native livers (I-FABP analyses, n = 21). Serum Gal-3 and I-FABP were analyzed using enzyme linked immunosorbent assay. Kidney disease severity variables included estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV). Liver disease severity was characterized using ultrasound elastography to measure liver fibrosis, and spleen length and platelet count as markers of portal hypertension. Simple and multivariable linear regression examined associations between Gal-3 and kidney disease severity (adjusted for liver disease severity) and between I-FABP and liver disease severity (adjusted for eGFR).
RESULTS: Serum Gal-3 was negatively associated with eGFR; 1 standard deviation (SD) lower eGFR was associated with 0.795 SD higher Gal-3 level (95% CI - 1.116, - 0.473; p < 0.001). This association remained significant when adjusted for liver disease severity. Serum Gal-3 was not associated with htTKV in adjusted analyses. Overall I-FABP levels were elevated, but there were no linear associations between I-FABP and liver disease severity in unadjusted or adjusted models.
CONCLUSIONS: Serum Gal-3 is associated with eGFR in ARPKD, suggesting its value as a possible novel biomarker of kidney disease severity. We found no associations between serum I-FABP and ARPKD liver disease severity despite overall elevated I-FABP levels.

Keywords:  Autosomal recessive polycystic kidney disease; Biomarkers; Chronic kidney disease; Congenital hepatic fibrosis; Portal hypertension; Ultrasound elastography

DOI:  https://doi.org/10.1007/s40620-022-01416-8
Bio Protoc. 2022 Jul 20. pii: e4467. [Epub ahead of print]12(14):

Purification and Immunostaining of Mouse Ependymal Ciliary Shafts.

Kai Hao, Xueliang Zhu, Xiumin Yan.

  Cilia and flagella are microtubule-based hair-like organelles protruding from the surface of most eukaryotic cells, and play essential roles in cell locomotion, left-right asymmetry, embryo development, and tissue homeostasis. With isolated cilia and flagella, great progress has been made in understanding the composition, structure, and function of cilia. However, the current cilia/flagella isolation methods are deficient in the integrity or productivity of purified cilia when applied to mammalian motile cilia. Here, we describe a new protocol that isolates cilia shafts from mouse ependymal cells, by horizontal shear force and mild detergent. This method enables the production of virtually integral cilia with high yields and less cell body contamination. It is suitable for immunostaining, puromycin labeling assay, and proximity ligation assay of mammalian motile cilia. Graphical abstract.

Keywords:   Ciliary shaft purification ; Ependymal cells ; Immunostaining ; Mammalian ; Motile cilia

DOI:  https://doi.org/10.21769/BioProtoc.4467
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2207134119

DYF-5/MAK-dependent phosphorylation promotes ciliary tubulin unloading.

Xuguang Jiang, Wenxin Shao, Yongping Chai, Jingying Huang, Mohamed A A Mohamed, Zeynep Ökten, Wei Li, Zhiwen Zhu, Guangshuo Ou.

Cilia are microtubule-based organelles that power cell motility and regulate sensation and signaling, and abnormal ciliary structure and function cause various ciliopathies. Cilium formation and maintenance requires intraflagellar transport (IFT), during which the kinesin-2 family motor proteins ferry IFT particles carrying axonemal precursors such as tubulins into cilia. Tubulin dimers are loaded to IFT machinery through an interaction between tubulin and the IFT-74/81 module; however, little is known of how tubulins are unloaded when arriving at the ciliary tip. Here, we show that the ciliary kinase DYF-5/MAK phosphorylates multiple sites within the tubulin-binding module of IFT-74, reducing the tubulin-binding affinity of IFT-74/81 approximately sixfold. Ablation or constitutive activation of IFT-74 phosphorylation abnormally elongates or shortens sensory cilia in Caenorhabditis elegans neurons. We propose that DYF-5/MAK-dependent phosphorylation plays a fundamental role in ciliogenesis by regulating tubulin unloading.

DOI: https://doi.org/10.1073/pnas.2207134119
Indian J Nucl Med. 2022 Apr-Jun;37(2):37(2): 172-174

Renal Dynamic Scintigraphy as a Sensitive Tool for Detecting Small Volume Urinoma Following Live-Related Renal Transplant.

Shubha Gadde Ravindra, Sumit Garg, Rakesh Kumar, Sambit Sagar, Aditi Khurana, Sandeep Aggarwal, Siba Narayan Padhi, Chekuri Ritwik.

  Renal transplant (RT) is the preferred treatment modality in patients with end-stage renal disease (ESRD). However, it is associated with a significant rate of complications. Early diagnosis and management of these complications are essential to prevent graft loss. Herein, we describe a case of a 48-year-old male who developed ESRD due to underlying autosomal-dominant polycystic kidney disease and underwent an RT. A routine renal dynamic scintigraphy (RDS) performed on day 4 posttransplant showed a focal minute area of radiotracer accumulation on the delayed static images raising suspicion for urinoma. However, it was deemed normal considering the normal renogram curve and stable clinical condition of the patient. However, on day 9 posttransplant, in view of clinical deterioration marked by decreasing urine output and rising serum creatinine levels, ultrasonography - kidney, ureter, and bladder (USG-KUB) and a repeat RDS were performed. Although the USG-KUB described a peri-nephric fluid collection, the nature of the collection could not be determined. RDS confirmed that the collection was urinoma. On retrospective analysis, the focal area of increased radiotracer uptake corresponded to the site of initial suspicion, although there was an increase in the size of the same. In experienced hands, RDS thus proves to be a highly sensitive tool for the diagnosis of urinoma, much before the clinical complications set in.

Keywords:   urinoma; Autosomal-dominant polycystic kidney disease; end-stage renal disease; renal dynamic scan; renal transplant

DOI:  https://doi.org/10.4103/ijnm.ijnm_168_21
Genet Med. 2022 Aug 17. pii: S1098-3600(22)00842-5. [Epub ahead of print]

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

Alexander M Holtz, Rachel Vancoil, Elizabeth A Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J Guillen Sacoto, Yue Si, Ingrid M Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H Sherr, Kimberly A Aldinger, William B Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A Donald, Emily O'Heir, Shade Moody, Katherine H Kim, Barbara K Burton, Grace Yoon, Miguel Del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L Sell, Patricia L Gordon, Jeremy W Prokop, Amel Karaa, Caleb Bupp, Benjamin A Raby.

   PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.
METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.
RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length.
CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Keywords:  Hedgehog signaling; MYH10; Neurodevelopmental disorder; Nonmuscle myosin; Primary cilia

DOI:  https://doi.org/10.1016/j.gim.2022.07.005
J Mol Cell Biol. 2022 Aug 18. pii: mjac049. [Epub ahead of print]

Cilia regulate meiotic recombination in zebrafish.

Haibo Xie, Xiaosi Wang, Minjun Jin, Lanqin Li, Junwen Zhu, Yunsi Kang, Zhe Chen, Yonghua Sun, Chengtian Zha.

  Meiosis is essential for evolution and genetic diversity in almost all sexual eukaryotic organisms. The mechanisms of meiotic recombination, such as synapsis, have been extensively investigated. However, it is still unclear whether signals from the cytoplasm or even from outside of the cell can regulate the meiosis process. Cilia are microtubule-based structures that protrude from cell surface and function as signaling hubs to sense extracellular signals. Here, we reported an unexpected and critical role of cilia during meiotic recombination. During gametogenesis of zebrafish, cilia were specifically present in the prophase stages of both primary spermatocytes and primary oocytes. By developing a germ cell-specific CRISPR/Cas9 system, we demonstrated that germ cell-specific depletion of ciliary genes resulted in compromised double-strand break repair, reduced crossover formation, and increased germ cell apoptosis. Our study reveals a previously undiscovered role for cilia during meiosis and suggests that extracellular signals may regulate meiotic recombination via this particular organelle.

Keywords:   kif3a ; cilia; homologous recombination; meiosis; zebrafish

DOI:  https://doi.org/10.1093/jmcb/mjac049
Osteoporos Int. 2022 Aug 18.

Romosozumab successfully regulated progressive osteoporosis in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis.

Taihei Suzuki, Masahide Mizobuchi, Shunsuke Yoshida, Narumi Terado, Shugo Aoki, Nozomi Sato, Hirokazu Honda.

  Osteoporosis is a crucial complication in patients with chronic kidney disease (CKD), similar to that in the general population. Although romosozumab, a monoclonal antibody targeting sclerostin, has been administered for patients with CKD, its clinical effectiveness in these patients, especially in patients on hemodialysis (HD), remains to be studied. Herein, we report the case of a 42-year-old man on HD who developed severe osteoporosis. Serum calcium levels were extremely high, bone metabolic markers were abnormal, and the patient had pathological fractures. The bone biopsy indicated a bone metabolism disorder and high bone turnover. We administered romosozumab once a month as an intervention for bone alteration. Through the 10-month usage, bone metabolic markers improved, and the decrease in bone mineral density was ameliorated. We hypothesized that romosozumab could be a therapeutic option for osteoporosis in patients undergoing HD, especially in those with bone mineralization disorders.

Keywords:  CKD-MBD; Hemodialysis; Osteoporosis; Renal osteodystrophy; Romosozumab

DOI:  https://doi.org/10.1007/s00198-022-06534-4