bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒05‒30
thirteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

  1. Clin J Gastroenterol. 2021 May 24.
      A 60-year-old man with autosomal dominant polycystic kidney disease presented with malaise, melena, and epigastric discomfort. Esophagogastroduodenoscopy revealed a massive elevated gastric cancer lesion involving the cardia. Histopathological evaluation of a biopsy specimen showed poorly differentiated adenocarcinoma. Fluorodeoxyglucose-positron emission tomography revealed significant fluorodeoxyglucose uptake in the stomach, liver, bones, and bone marrow. He was diagnosed with metastatic gastric cancer resistant to chemotherapy, and he developed bone marrow carcinomatosis and disseminated intravascular coagulation and died 8 weeks after disease onset. A statistically significant association is reported between autosomal dominant polycystic kidney disease and gastric cancer. Moreover, the specific clinical features observed in our patient could be attributed to the molecular disorders like PC-1 and mechanistic target of rapamycin that are known to occur in autosomal dominant polycystic kidney disease.
    Keywords:  Autosomal dominant polycystic kidney disease; Gastric cancer; Mechanistic target of rapamycin; PKD-1 gene; Polycystin-1
  2. PLoS One. 2021 ;16(5): e0252479
      Pain is a common symptom in people with autosomal dominant polycystic kidney disease (ADPKD), but it is assessed and reported inconsistently in research, and the validity of the measures remain uncertain. The aim of this study was to identify the characteristics, content, and psychometric properties of measures for pain used in ADPKD. We conducted a systematic review including all trials and observational studies that reported pain in people with ADPKD. Items from all measures were categorized into content and measurement dimensions of pain. We assessed the general characteristics and psychometric properties of all measures. 118 studies, we identified 26 measures: 12 (46%) measures were developed for a non-ADPKD population, 1 (4%) for chronic kidney disease, 2 (8%) for polycystic liver disease and 11 (42%) specifically for ADPKD. Ten anatomical sites were included, with the lower back the most common (10 measures [39%]), four measurement dimensions (intensity (23 [88%]), frequency (3 [12%]), temporality (2 [8%]), and sensory (21 [81%]), two pain types, nociceptive including visceral (15 [58%]) and somatic (5 [20%]), and neuropathic (2 [8%]), and twelve impact dimensions, where the most frequent was work (5 [31%]). The validation data for the measures were variable and only the ADPKD Impact Scale reported all psychometric domains. The measures for pain in ADPKD varied in terms of content and length, and most had not been validated in ADPKD. A standardized psychometrically robust measure that captures patient-important dimensions of pain is needed to evaluate and manage this debilitating complication of ADPKD.
  3. J Cell Mol Med. 2021 May 25.
      Polycystic kidney disease (PKD) is known to occur in three main forms, namely autosomal dominant PKD (ADPKD), autosomal recessive PKD (ARPKD) and syndromic PKD (SPKD), based on the clinical manifestations and genetic causes, which are diagnosable from the embryo stage to the later stages of life. Selection of the genetic test for the individuals with diagnostic imaging reports of cystic kidneys without a family history of the disease continues to be a challenge in clinical practice. With the objective of maintaining a limit on the time and medical cost of the procedure, a practical strategy for genotyping and targeted validation to resolve cystogene variations was developed in our clinical laboratory, which combined the techniques of whole-exome sequencing (WES), Long-range PCR (LR-PCR), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to work in a stepwise approach. In this context, twenty-six families with renal polycystic disorders were enrolled in the present study. Thirty-two variants involving four ciliary genes (PKD1, PKHD1, TMEM67 and TMEM107) were identified and verified in 23 families (88.5%, 23/26), which expanded the variant spectrum by 16 novel variants. Pathogenic variations in five foetuses of six families diagnosed with PKD were identified using prenatal ultrasound imaging. Constitutional biallelic and digenic variations constituted the pathogenic patterns in these foetuses. The preliminary clinical data highlighted that the WES + LR PCR-based workflow followed in the present study is efficient in detecting divergent variations in PKD. The biallelic and digenic mutations were revealed as the main pathogenic patterns in the foetuses with PKD.
    Keywords:   PKD1 ; PKHD1 ; TMEM107 ; TMEM67 ; long-range PCR; polycystic kidney disease; whole-exome sequencing
  4. Urol Case Rep. 2021 Sep;38 101701
      We present a very rare Case of a 53-year-old female with autosomal dominant polycystic kidney disease (ADPKD) who was incidentally found to have a reno-appendiceal fistula while undergoing open bilateral nephrectomy. The mid-portion of the appendix was fistulized to a cyst in the lower pole of the right kidney. The etiology was likely due to chronic inflammation. An appendectomy was performed along with the planned right nephrectomy to ensure complete removal of the fistulous tract.
    Keywords:  ADPK, Dautosomal dominant polycystic kidney disease; Appendix; Autosomal dominant polycystic kidney disease; Fistula; Reno-alimentary fistula; UTI, urinary tract infection
  5. BMC Nephrol. 2021 May 24. 22(1): 194
      BACKGROUND: The Kidney Failure Risk Equation (KFRE) predicts the 2- and 5-year risk of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD) stages 3a-5. Its predictive performance in advanced CKD and in specific disease aetiologies requires further exploration. This study validates the 4- and 8-variable KFREs in an advanced CKD population in the United Kingdom by evaluating discrimination, calibration and clinical utility.METHODS: Patients enrolled in the Salford Kidney Study who were referred to the Advanced Kidney Care Service (AKCS) clinic at Salford Royal NHS Foundation Trust between 2011 and 2018 were included. The 4- and 8-variable KFREs were calculated on the first AKCS visit and the observed events of ESRD (dialysis or pre-emptive transplantation) within 2- and 5-years were the primary outcome. The area under the receiver operator characteristic curve (AUC) and calibration plots were used to evaluate discrimination and calibration respectively in the whole cohort and in specific disease aetiologies: diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and other diseases. Clinical utility was assessed with decision curve analyses, comparing the net benefit of using the KFREs against estimated glomerular filtration rate (eGFR) cut-offs of < 20 ml/min/1.73m2 and < 15 ml/min/1.73m2 to guide further treatment.
    RESULTS: A total of 743 patients comprised the 2-year analysis and 613 patients were in the 5-year analysis. Discrimination was good in the whole cohort: the 4-variable KFRE had an AUC of 0.796 (95% confidence interval [CI] 0.762-0.831) for predicting ESRD at 2-years and 0.773 (95% CI 0.736-0.810) at 5-years, and there was good-to-excellent discrimination across disease aetiologies. Calibration plots revealed underestimation of risk at 2-years and overestimation of risk at 5-years, especially in high-risk patients. There was, however, underestimation of risk in patients with ADPKD for all KFRE calculations. The predictive accuracy was similar between the 4- and 8-variable KFREs. Finally, compared to eGFR-based thresholds, the KFRE was the optimal tool to guide further care based on decision curve analyses.
    CONCLUSIONS: The 4- and 8-variable KFREs demonstrate adequate discrimination and calibration for predicting ESRD in an advanced CKD population and, importantly, can provide better clinical utility than using an eGFR-based strategy to inform decision-making.
    Keywords:  Calibration; Chronic kidney disease; Decision curve analysis; Discrimination; End-stage renal disease; Kidney failure risk equation; Risk prediction
  6. Pflugers Arch. 2021 May 28.
      The rod and cone photoreceptor cells of the vertebrate retina have highly specialized structures that enable them to carry out their function of light detection over a broad range of illumination intensities with optimized spatial and temporal resolution. Most prominent are their unusually large sensory cilia, consisting of outer segments packed with photosensitive disc membranes, a connecting cilium with many features reminiscent of the primary cilium transition zone, and a pair of centrioles forming a basal body which serves as the platform upon which the ciliary axoneme is assembled. These structures form a highway through which an enormous flux of material moves on a daily basis to sustain the continual turnover of outer segment discs and the energetic demands of phototransduction. After decades of study, the details of the fine structure and distribution of molecular components of these structures are still incompletely understood, but recent advances in cellular imaging techniques and animal models of inherited ciliary defects are yielding important new insights. This knowledge informs our understanding both of the mechanisms of trafficking and assembly and of the pathophysiological mechanisms of human blinding ciliopathies.
    Keywords:  Ciliopathies; Cones; Cytoskeleton; Electron microscopy; Photoreceptors; Primary cilia; Retina; Rods; Superresolution fluorescence
  7. Andrologia. 2021 May 27. e14124
      Polycystin-2, also known as transient receptor potential polycystin-2 (TRPP2), is a membrane protein that regulates calcium homeostasis in renal epithelial cells. Mutations in PKD2, the gene encoding human TRPP2, cause enlarged cystic kidneys and contribute to polycystic kidney disease (PKD). Male Drosophila melanogaster with mutations in amo, the homolog of PKD2, display a mild decrease in sperm motility but have a drastic reduction in fertility due to failed sperm migration and storage within the female tract. Although TRPP2 has critical roles for Drosophila sperm function, the protein has not been described in mammalian sperm. Herein, we report the localization of TRPP2 in porcine sperm and identify functions of TRPP2 in regulating intracellular Ca2+ and motility. Porcine sperm treated with an antibody to TRPP2 in capacitating medium had reduced average path velocity and curvilinear velocity (p < .05). Blocking TRPP2 also increased sperm tail beat-cross frequency (p < .05). After 90 min of capacitation, sperm incubated with TRPP2 antibody had decreased intracellular Ca2+ concentration compared to controls (p < .05), consistent with TRPP2 function as a plasma membrane cation channel. This is the first report that mammalian sperm contain TRPP2, which appears to regulate intracellular Ca2+ and motility patterns in porcine sperm.
    Keywords:  PKD2; boar; calcium; motility; sperm
  8. Tissue Eng Part B Rev. 2021 May 27.
      Rho-associated protein kinases (ROCK) affect a variety of cellular functions including cell attachment, migration, and proliferation. ROCK inhibitors therefore have potential as tools for optimising cell behaviour in tissue engineering applications, including the manufacturing of cultivated epithelial autografts (CEA) used in the treatment of burns patients. For example, ROCK inhibitors may facilitate earlier engraftment of CEA sheets by increasing the proliferation of skin keratinocytes ex vivo. Nevertheless, the current understanding of ROCK inhibitor action on epidermal keratinocytes is unclear owing to multiple drug formulations, drug concentrations, and cellular function assays having been used. The aim of this review paper therefore is to identify consistent patterns of ROCK inhibitor action on human keratinocytes as well as revealing key knowledge gaps. In doing so we propose a clearer course of action for pursuing the potential benefits of ROCK inhibitors for the future treatment of burns patients.
  9. Curr Biol. 2021 May 24. pii: S0960-9822(21)00454-1. [Epub ahead of print]31(10): R530-R536
      Cells need to be able to sense different types of signals, such as chemical and mechanical stimuli, from the extracellular environment in order to properly function. Most eukaryotic cells sense these signals in part through a specialized hair-like organelle, the cilium, that extends from the cell body as a sort of antenna. The signaling and sensory functions of cilia are fundamental during the early stages of embryonic development, when cilia coordinate the establishment of the internal left-right asymmetry that is typical of the vertebrate body. Later, cilia continue to be required for the correct development and function of specific tissues and organs, such as the brain, heart, kidney, liver, and pancreas. Sensory cilia allow us to sense the environment that surrounds us; for instance, we see as a result of the connecting cilia of photoreceptors in our retina, we smell through the sensory cilia at the tips of our olfactory neurons, and we hear thanks to the kinocilia of our sensory hair cells. Motile cilia, which themselves have sensory functions, also work as propeller-like extensions that allow us to breathe because they keep our lungs clean, to reproduce because they propel sperm cells, and even to properly reason because they contribute to the flow of cerebrospinal fluid in our brain ventricles. Not surprisingly, defects in the assembly and function of these tiny organelles result in devastating pathologies, collectively known as ciliopathies (Box 1). Thus, the proper function of cilia is fundamental for human health.
  10. J Cell Physiol. 2021 May 28.
      Yes-associated protein (YAP) and PDZ-binding motif (TAZ) have emerged as important regulators of pathologic fibroblast activation in fibrotic diseases. Agonism of Gαs-coupled G protein coupled receptors (GPCRs) provides an attractive approach to inhibit the nuclear localization and function of YAP and TAZ in fibroblasts that inhibits or reverses their pathological activation. Agonism of the dopamine D1 GPCR has proven effective in preclinical models of lung and liver fibrosis. However, the molecular mechanisms coupling GPCR agonism to YAP and TAZ inactivation in fibroblasts remain incompletely understood. Here, using human lung fibroblasts, we identify critical roles for the cAMP effectors EPAC1/2, the small GTPase RAP2c, and the serine/threonine kinase MAP4K7 as the essential elements in the downstream signaling cascade linking GPCR agonism to LATS1/2-mediated YAP and TAZ phosphorylation and nuclear exclusion in fibroblasts. We further show that this EPAC/RAP2c/MAP4K7 signaling cascade is essential to the effects of dopamine D1 receptor agonism on reducing fibroblast proliferation, contraction, and extracellular matrix production. Targeted modulation of this cascade in fibroblasts may prove a useful strategy to regulate YAP and TAZ signaling and fibroblast activities central to tissue repair and fibrosis.
    Keywords:  DRD1; Hippo; cAMP; dihydrexidine; dopamine; fibrosis
  11. Neurochem Res. 2021 May 23.
      Although antipsychotics are routinely used in the treatment of schizophrenia for the last decades, their precise mechanism of action is still unclear. In this study, we investigated changes in the PC12 cells' proteome under the influence of clozapine, risperidone, and haloperidol to identify protein pathways regulated by antipsychotics. Analysis of the protein profiles in two time points: after 12 and 24 h of incubation with drugs revealed significant alterations in 510 proteins. Further canonical pathway analysis revealed an inhibition of ciliary trophic factor signaling after treatment with haloperidol and showed a decrease in acute phase response signaling in the risperidone group. Interestingly, all tested drugs have caused changes in PC12 proteome which correspond to inhibition of cytokines: tumor necrosis factor (TNF) and transforming growth factor beta 1 (TGF-β1). We also found that the 12-h incubation with clozapine caused up-regulation of protein kinase A signaling and translation machinery. After 24 h of treatment with clozapine, the inhibition of the actin cytoskeleton signaling and Rho proteins signaling was revealed. The obtained results suggest that the mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) play a central role in the signal transduction of clozapine.
    Keywords:  Actin signaling; Antipsychotic drugs; Clozapine; Proteome; Translation; mTOR
  12. J Neurochem. 2021 May 25.
      Postoperative delirium (POD) is a common postoperative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood cerebrospinal fluid barrier (BCB) and brain blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2A R), a key regulator of the permeability of barriers, on surgery-induced increased permeability of BCB and POD-like behaviors. Open field, buried food and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2A R, GTP-RhoA and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC-dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO-1, occludin and claudin1) proteins, increased concentrations of NaFI and FITC-dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD-like behaviors in rats. An A2A R antagonist alleviated POD-like behaviors in rats. Furthermore, the A2A R antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho-associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD-like behaviors induced by A2A R activation. Moreover, fasudil also abolished the increased levels of GTP-RhoA/ROCK2, decreased levels of tight junction proteins and increased permeability of BCB caused by A2A R activation. Our findings demonstrate that A2A R might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2A R as a therapeutic target for POD.
    Keywords:  Adenosine A2A receptor; Blood cerebrospinal barrier; Postoperative delirium; Rho-associated protein kinase 2; RhoA
  13. Curr Biol. 2021 May 24. pii: S0960-9822(21)00075-0. [Epub ahead of print]31(10): R506-R511
      Encircling and traversing the cell are architectural struts and dynamic intracellular highways made of cylindrical polymers called microtubules. Built from structurally asymmetric subunits of αβ-tubulin heterodimers, microtubules have an inherent structural polarity with a slow-growing minus end and a comparatively dynamic plus end that grows and shrinks. Thus, a key feature of microtubules is that each polymer is polarized, allowing for the execution of cellular tasks that are directional in nature. For example, microtubules build polarized highways allowing directional intracellular transport, generate directional force such as in chromosome alignment and segregation, provide structural support for cell shape, and assemble into highly ordered polar structures like centrioles and cilia. The output of these microtubule-based functions is the performance of different tasks, including establishment and maintenance of cellular polarity, secretion and absorption, cell-cell communication, migration, mechanical resiliency, and mitosis. Different cells accomplish these functions by using distinct sites within the cell called microtubule-organizing centers (MTOCs) to build cell-specific microtubule arrangements. While the specific requirement for microtubules in many in vivo cell types is unknown, disrupting even a subset of microtubule-supported functions is often lethal and is associated with many diseases (e.g., cancer and neuropathies), suggesting that specific patterns of microtubule organization are likely important for cellular function in vivo. This Primer focuses on how differentiated animal and plant cells use distinct MTOCs to generate specific microtubule arrangements, how those arrangements support cellular functions, and how cells rearrange their microtubules to accommodate changing cellular tasks.