bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–05–22
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Molecular Mechanisms of Isolated Polycystic Liver Diseases.
  2. A Case Report of Tuberous Sclerosis and Autosomal Dominant Polycystic Kidney Disease in the Era of Tolvaptan.
  3. Asymptomatic Pyuria as a Prognostic Biomarker in Autosomal Dominant Polycystic Kidney Disease.
  4. Roles of the actin cytoskeleton in ciliogenesis.
  5. Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD.
  6. Ciliary central apparatus structure reveals mechanisms of microtubule patterning.
  7. The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling.
  8. Benzodiazepine Derivatives as Potent Vasopressin V2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.
  9. Cryo-EM structure of an active central apparatus.
  10. Two Cases With Neonatal Cholestasis and Renal Disorders Due to DCDC2 Mutation.
  11. Cilia are not created equal-restriction of IFT on microtubule tracks for cilia diversification.
  12. ECM stiffness modulates the proliferation but not the motility of primary corneal keratocytes in response to PDGF-BB.
  1. Front Genet. 2022 ;13 846877
    Molecular Mechanisms of Isolated Polycystic Liver Diseases.
    Ziqi Yu, Xiang Shen, Chong Hu, Jun Zeng, Aiyao Wang, Jianyong Chen.
      Polycystic liver disease (PLD) is a rare autosomal dominant disorder including two genetically and clinically distinct forms: autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). The main manifestation of ADPKD is kidney cysts, while PCLD has predominantly liver presentations with mild or absent kidney cysts. Over the past decade, PRKCSH, SEC63, ALG8, and LRP5 have been candidate genes of PCLD. Recently, more candidate genes such as GANAB, SEC61B, and ALR9 were also reported in PCLD patients. This review focused on all candidate genes of PCLD, including the newly established novel candidate genes. In addition, we also discussed some other genes which might also contribute to the disease.
    Keywords:  LRP5; PCLD; PLD; PRKCSH; Sec63; alg8; polycystic liver disease
    DOI:  https://doi.org/10.3389/fgene.2022.846877
  2. Curr Rev Clin Exp Pharmacol. 2022 May 17.
    A Case Report of Tuberous Sclerosis and Autosomal Dominant Polycystic Kidney Disease in the Era of Tolvaptan.
    Xavier E Guerra-Torres.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) may coexist with other genetic disorders, such as tuberous sclerosis, when deletion in TSC2/PKD1 genes occurs. Recently, the effect of tolvaptan has been explored in ADPKD patients alone, but its safety and efficacy on TSC2/PKD1 contiguous gene syndrome is unknown.
    CASE PRESENTATION: This report describes the case of an asymptomatic patient with TSC2/PKD1 contiguous gene syndrome that fulfills the imaging criteria for initiating the treatment with tolvaptan. After twelve months, the patient did not exhibit severe adverse effects and blood pressure control improved.
    CONCLUSION: In this TSC2/PKD1 contiguous gene syndrome single case report, tolvaptan was safe and well-tolerated. More extensive experimental studies are needed to deeply understand the therapeutic implications of vasopressin V2-receptor inhibition in the TSC2/PKD1 contiguous gene syndrome patients.
    Keywords:  Autosomal dominant polycystic kidney disease; TSC2/PKD1 contiguous gene syndrome; tolvaptan; tuberous sclerosis; tuberous sclerosis complex; vasopressin antagonist
    DOI:  https://doi.org/10.2174/2772432817666220517162012
  3. Kidney360. 2022 Mar 31. 3(3): 465-476
    Asymptomatic Pyuria as a Prognostic Biomarker in Autosomal Dominant Polycystic Kidney Disease.
    Brian E Jones, Yaman G Mkhaimer, Laureano J Rangel, Maroun Chedid, Phillip J Schulte, Alaa K Mohamed, Reem M Neal, Dalia Zubidat, Amarjyot K Randhawa, Christian Hanna, Adriana V Gregory, Timothy L Kline, Ziad M Zoghby, Sarah R Senum, Peter C Harris, Vicente E Torres, Fouad T Chebib.
       Background: Autosomal dominant polycystic kidney disease (ADPKD) has phenotypic variability only partially explained by established biomarkers that do not readily assess pathologically important factors of inflammation and kidney fibrosis. We evaluated asymptomatic pyuria (AP), a surrogate marker of inflammation, as a biomarker for disease progression.
    Methods: We performed a retrospective cohort study of adult patients with ADPKD. Patients were divided into AP and no pyuria (NP) groups. We evaluated the effect of pyuria on kidney function and kidney volume. Longitudinal models evaluating kidney function and kidney volume rate of change with respect to incidences of AP were created.
    Results: There were 687 included patients (347 AP, 340 NP). The AP group had more women (65% versus 49%). Median ages at kidney failure were 86 and 80 years in the NP and AP groups (log rank, P=0.49), respectively, for patients in Mayo Imaging Class (MIC) 1A-1B as compared with 59 and 55 years for patients in MIC 1C-1D-1E (log rank, P=0.02), respectively. Compared with the NP group, the rate of kidney function (ml/min per 1.73 m2 per year) decline shifted significantly after detection of AP in the models, including all patients (-1.48; P<0.001), patients in MIC 1A-1B (-1.79; P<0.001), patients in MIC 1C-1D-1E (-1.18; P<0.001), and patients with PKD1 (-1.04; P<0.001). Models evaluating kidney volume rate of growth showed no change after incidence of AP as compared with the NP group.
    Conclusions: AP is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene, cystic burden, and cystic growth. These results support AP as an enriching prognostic biomarker for the rate of disease progression.
    Keywords:  ADPKD; biomarkers; chronic inflammation; cystic kidney disease; disease stratification; glomerular filtration rate; polycystic kidney disease; prognosis; pyuria; rapid progression
    DOI:  https://doi.org/10.34067/KID.0004292021
  4. J Cell Sci. 2022 May 15. pii: jcs259030. [Epub ahead of print]135(10):
    Roles of the actin cytoskeleton in ciliogenesis.
    Huxley K Hoffman, Rytis Prekeris.
      Primary cilia play a key role in the ability of cells to respond to extracellular stimuli, such as signaling molecules and environmental cues. These sensory organelles are crucial to the development of many organ systems, and defects in primary ciliogenesis lead to multisystemic genetic disorders, known as ciliopathies. Here, we review recent advances in the understanding of several key aspects of the regulation of ciliogenesis. Primary ciliogenesis is thought to take different pathways depending on cell type, and some recent studies shed new light on the cell-type-specific mechanisms regulating ciliogenesis at the apical surface in polarized epithelial cells, which are particularly relevant for many ciliopathies. Furthermore, recent findings have demonstrated the importance of actin cytoskeleton dynamics in positively and negatively regulating multiple stages of ciliogenesis, including the vesicular trafficking of ciliary components and the positioning and docking of the basal body. Finally, studies on the formation of motile cilia in multiciliated epithelial cells have revealed requirements for actin remodeling in this process too, as well as showing evidence of an additional alternative ciliogenesis pathway.
    Keywords:  Actin; Cilia; Epithelial cell
    DOI:  https://doi.org/10.1242/jcs.259030
  5. Kidney Int Rep. 2022 May;7(5): 1037-1048
    Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD.
    Xiaolei Zhou, Eric Davenport, John Ouyang, Molly E Hoke, Diana Garbinsky, Indra Agarwal, Holly B Krasa, Dorothee Oberdhan.
       Introduction: In 1- and 3-year randomized trials, tolvaptan slowed kidney function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. The 3-year trial also evaluated effects on total kidney volume (TKV); slowing of TKV growth was demonstrated. Subjects were followed in open-label extension trials. To characterize longer-term effects of treatment, an analysis was conducted comparing tolvaptan-treated subjects with subjects from standard of care (SOC) ADPKD studies without tolvaptan.
    Methods: This was a pooled, longitudinal analysis of data from 8 tolvaptan clinical trials and 5 studies without tolvaptan (natural history or SOC) in ADPKD. Data from subjects who participated in multiple studies were linked for longer follow-up. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and TKV over 5.5 years. To control for heterogeneity in disease characteristics between tolvaptan and SOC treatment groups, analysis populations matched for baseline demographic and disease characteristics were constructed.
    Results: Matched analysis (n = 1186 in each treatment group) indicated that tolvaptan slowed annualized eGFR decline by 1.01 ml/min per 1.73 m2 (P < 0.001) versus SOC over 5.5 years. An analysis conducted on the full, unmatched data set (tolvaptan: n = 2928; SOC: n = 4189) confirmed significant reduction in annual eGFR decline. Among subjects with TKV data, TKV was significantly reduced at years 1, 3, and 5 for tolvaptan versus SOC in both matched and full data sets.
    Conclusion: Comparison of a pooled tolvaptan cohort to a pooled control cohort with ADPKD supports longer-term treatment effects of tolvaptan.
    Keywords:  autosomal dominant polycystic kidney disease (ADPKD); glomerular filtration rate; kidney function; longitudinal; tolvaptan; total kidney volume
    DOI:  https://doi.org/10.1016/j.ekir.2022.02.009
  6. Nat Struct Mol Biol. 2022 May;29(5): 483-492
    Ciliary central apparatus structure reveals mechanisms of microtubule patterning.
    Miao Gui, Xiangli Wang, Susan K Dutcher, Alan Brown, Rui Zhang.
      A pair of extensively modified microtubules form the central apparatus (CA) of the axoneme of most motile cilia, where they regulate ciliary motility. The external surfaces of both CA microtubules are patterned asymmetrically with large protein complexes that repeat every 16 or 32 nm. The composition of these projections and the mechanisms that establish asymmetry and longitudinal periodicity are unknown. Here, by determining cryo-EM structures of the CA microtubules, we identify 48 different CA-associated proteins, which in turn reveal mechanisms for asymmetric and periodic protein binding to microtubules. We identify arc-MIPs, a novel class of microtubule inner protein, that bind laterally across protofilaments and remodel tubulin structure and lattice contacts. The binding mechanisms utilized by CA proteins may be generalizable to other microtubule-associated proteins. These structures establish a foundation to elucidate the contributions of individual CA proteins to ciliary motility and ciliopathies.
    DOI:  https://doi.org/10.1038/s41594-022-00770-2
  7. Cell Rep. 2022 May 17. pii: S2211-1247(22)00582-4. [Epub ahead of print]39(7): 110811
    The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic hedgehog signaling.
    Leah Schembs, Ariane Willems, Kerstin Hasenpusch-Theil, James D Cooper, Katie Whiting, Karen Burr, Sunniva M K Bøstrand, Bhuvaneish T Selvaraj, Siddharthan Chandran, Thomas Theil.
      Defects in primary cilia, cellular antennas that control multiple intracellular signaling pathways, underlie several neurodevelopmental disorders, but it remains unknown how cilia control essential steps in human brain formation. Here, we show that cilia are present on the apical surface of radial glial cells in human fetal forebrain. Interfering with cilia signaling in human organoids by mutating the INPP5E gene leads to the formation of ventral telencephalic cell types instead of cortical progenitors and neurons. INPP5E mutant organoids also show increased Sonic hedgehog (SHH) signaling, and cyclopamine treatment partially rescues this ventralization. In addition, ciliary expression of SMO, GLI2, GPR161, and several intraflagellar transport (IFT) proteins is increased. Overall, these findings establish the importance of primary cilia for dorsal and ventral patterning in human corticogenesis, indicate a tissue-specific role of INPP5E as a negative regulator of SHH signaling, and have implications for the emerging roles of cilia in the pathogenesis of neurodevelopmental disorders.
    Keywords:  CP: Neuroscience; INPP5E; dorsal and ventral patterning; human cortex; primary cilia; sonic hedgehog; telencephalon
    DOI:  https://doi.org/10.1016/j.celrep.2022.110811
  8. J Med Chem. 2022 May 17.
    Benzodiazepine Derivatives as Potent Vasopressin V2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.
    Xudong Cao, Peng Wang, Haoxing Yuan, Haoran Zhang, Yan He, Kequan Fu, Qian Fang, Hongli Liu, Limin Su, Long Yin, Pei Xu, Yuyang Xie, Xiaochun Xiong, Junqi Wang, Xu Zhu, Dong Guo.
      Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V2 receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25 exhibited potent binding affinity to the V2R (Ki = 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50 = 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound 25 in a murine model of ADPKD demonstrated a significantly improved in vivo efficacy compared with the reference compound tolvaptan. Overall, compound 25 holds therapeutic potential for the treatment of ADPKD.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c00567
  9. Nat Struct Mol Biol. 2022 May;29(5): 472-482
    Cryo-EM structure of an active central apparatus.
    Long Han, Qinhui Rao, Renbin Yang, Yue Wang, Pengxin Chai, Yong Xiong, Kai Zhang.
      Accurately regulated ciliary beating in time and space is critical for diverse cellular activities, which impact the survival and development of nearly all eukaryotic species. An essential beating regulator is the conserved central apparatus (CA) of motile cilia, composed of a pair of microtubules (C1 and C2) associated with hundreds of protein subunits per repeating unit. It is largely unclear how the CA plays its regulatory roles in ciliary motility. Here, we present high-resolution structures of Chlamydomonas reinhardtii CA by cryo-electron microscopy (cryo-EM) and its dynamic conformational behavior at multiple scales. The structures show how functionally related projection proteins of CA are clustered onto a spring-shaped scaffold of armadillo-repeat proteins, facilitated by elongated rachis-like proteins. The two halves of the CA are brought together by elastic chain-like bridge proteins to achieve coordinated activities. We captured an array of kinesin-like protein (KLP1) in two different stepping states, which are actively correlated with beating wave propagation of cilia. These findings establish a structural framework for understanding the role of the CA in cilia.
    DOI:  https://doi.org/10.1038/s41594-022-00769-9
  10. Exp Clin Transplant. 2022 May;20(Suppl 3): 115-117
    Two Cases With Neonatal Cholestasis and Renal Disorders Due to DCDC2 Mutation.
    Demet Teker Düztaş, Sinan Sarı, Ödül Eğritaş Gürkan, Gülsüm Kayhan, Aydın Dalgıç, Buket Dalgıç.
      Ciliopathies are a heterogeneous group of diseases that are observed after deterioration of the ciliary structures on the cell surface that facilitate communication with the environment. Both liver and kidney involvement are frequently observed in this disease. Recently, a doublecortin domain containing protein 2 (DCDC2) mutation in a ciliopathy disease group was identified. Here, we present 2 patients with this mutation and with neonatal cholestasis and renal involvement.
    DOI:  https://doi.org/10.6002/ect.PediatricSymp2022.O37
  11. Bioessays. 2022 May 20. e2200082
    Cilia are not created equal-restriction of IFT on microtubule tracks for cilia diversification.
    Junmin Pan.
      
    DOI:  https://doi.org/10.1002/bies.202200082
  12. Exp Eye Res. 2022 May 17. pii: S0014-4835(22)00192-0. [Epub ahead of print] 109112
    ECM stiffness modulates the proliferation but not the motility of primary corneal keratocytes in response to PDGF-BB.
    Krithika S Iyer, Daniel P Maruri, Kara E Peak, David W Schmidtke, W Matthew Petroll, Victor D Varner.
      During corneal wound healing, keratocytes present within the corneal stroma become activated into a repair phenotype upon the release of growth factors, such as transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). The process of injury and repair can lead to changes in the mechanical properties of the tissue, and previous work has shown that the TGF-β1-mediated myofibroblast differentiation of corneal keratocytes depends on substratum stiffness. It is still unclear, however, if changes in stiffness can modulate keratocyte behavior in response to other growth factors, such as PDGF-BB. Here, we used a polyacrylamide (PA) gel system to determine whether changes in stiffness influence the proliferation and motility of primary corneal keratocytes treated with PDGF-BB. In the presence of PDGF-BB, cells on stiffer substrata exhibited a more elongated morphology and had higher rates of proliferation than cells in a more compliant microenvironment. Using a freeze-injury to assay cell motility, however, we did not observe any stiffness-dependent differences in the migration of keratocytes treated with PDGF-BB. Taken together, these data highlight the importance of biophysical cues during corneal wound healing and suggest that keratocytes respond differently to changes in ECM stiffness in the presence of different growth factors.
    Keywords:  Biomechanics; Corneal wound healing; Freeze injury; Mechanobiology; Platelet-derived growth factor
    DOI:  https://doi.org/10.1016/j.exer.2022.109112
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