bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022‒12‒11
nine papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Considerations for genetic testing in individuals with autosomal dominant polycystic kidney disease.
  2. A rare cause of galactorrhea in autosomal dominant polycystic kidney disease: pituitary stalk compression by an intracranial aneurysm.
  3. A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.
  4. Renal primary cilia lengthen in the progression of diabetic kidney disease.
  5. H2S-mediated inhibition of RhoA/ROCK pathway and noncoding RNAs in ischemic stroke.
  6. Glomerular hyperfiltration: part 2-clinical significance in children.
  7. Critical role of Rho proteins in myosin light chain di-phosphorylation during early phase of endothelial barrier disruption.
  8. Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.
  9. IFT-A structure reveals carriages for membrane protein transport into cilia.
  1. J Am Assoc Nurse Pract. 2022 Dec 01. 34(12): 1249-1251
    Considerations for genetic testing in individuals with autosomal dominant polycystic kidney disease.
    Elyssa M Noce.
      ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a systemic, irreversible, genetic condition caused by mutations in the PKD1 and PKD2 genes, and the most common form of inherited kidney disease in the United States, affecting more than 600,000 individuals. Because the condition is autosomal dominant, there is a 50% chance that each child of an affected adult will also have the pathogenic genetic mutation. PKD1 mutation accounts for approximately 85% of ADPKD cases and is characterized by an earlier onset of disease with more rapid progression, whereas PKD2 mutation accounts for the remaining 15% of cases and is characterized by a less severe and less rapid disease course. Genetic testing is not consistently used in the management of individuals with ADPKD, although it can provide invaluable information regarding disease progression and prognosis. Genetic data are necessary to effectively communicate disease progression with patients, use current prognostic calculators, and play a role in family planning. Increasing clinician knowledge in primary care and nephrology providers will contribute to improved care for individuals affected by ADPKD.
    DOI:  https://doi.org/10.1097/JXX.0000000000000787
  2. Pol Arch Intern Med. 2022 Dec 05. pii: 16367. [Epub ahead of print]
    A rare cause of galactorrhea in autosomal dominant polycystic kidney disease: pituitary stalk compression by an intracranial aneurysm.
    Emilia Blomerus, Chandani Dayal, Malcolm Davies.
      
    DOI:  https://doi.org/10.20452/pamw.16367
  3. Liver Int. 2022 Dec 08.
    A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.
    Bernhard Schlevogt, Vincent Schlieper, Jana Krader, Rita Schröter, Thomas Wagner, Matthias Weiand, Andree Zibert, Hartmut H Schmidt, Carsten Bergmann, Pavel I Nedvetsky, Michael P Krahn.
      BACKGROUND & AIMS: Autosomal dominant polycystic liver and kidney disease is a spectrum of hereditary diseases which display disturbed function of primary cilia leading to cyst formation. In autosomal dominant polycystic kidney disease a genetic cause can be determined in almost all cases. However, in isolated polycystic liver disease about half of all cases remain genetically unsolved, suggesting more, so far unidentified genes to be implicated in this disease.METHODS: Customized next-generation sequencing was used to identify the underlying pathogenesis in two related patients with polycystic liver disease. A variant identified in SEC61A1 was further analyzed in immortalized patients' urine sediment cells and in an epithelial cell model.
    RESULTS: In both patients, a heterozygous missense change (c.706C>T / p.Arg236Cys) was found in SEC61A1, which encodes for a subunit of the translocation machinery of protein biosynthesis at the endoplasmic reticulum. While kidney disease is absent in the proposita, her mother displays an atypical polycystic kidney phenotype with severe renal failure. In immortalized urine sediment cells, mutant SEC61A1 is expressed at reduced levels, resulting in decreased levels of Polycystin-2 (PC2). In an epithelial cell culture model, we found the proteasomal degradation of mutant SEC61A1 to be increased, whereas its localization to the endoplasmic reticulum is not affected.
    CONCLUSIONS: Our data expands the allelic and clinical spectrum for SEC61A1, adding polycystic liver disease as a new and the major phenotypic trait in the family described. We further demonstrate that mutant SEC61A1 results in enhanced proteasomal degradation and impaired biosynthesis of PC2.
    Keywords:  SEC61 channelopathies; polycystic kidney disease; translocon; whole exome sequencing
    DOI:  https://doi.org/10.1111/liv.15493
  4. Front Endocrinol (Lausanne). 2022 ;13 984452
    Renal primary cilia lengthen in the progression of diabetic kidney disease.
    Yunfeng Bai, Ping Li, Jiaona Liu, Lu Zhang, Shaoyuan Cui, Cuiting Wei, Bo Fu, Xuefeng Sun, Guangyan Cai, Quan Hong, Xiangmei Chen.
      Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, and its early pathogenesis is critical. Shear stress caused by glomerular hyperfiltration contributes to the initiation of kidney injury in diabetes. The primary cilium of renal tubular epithelial cells (RTECs) is an important mechanical force sensor of shear stress and regulates energy metabolism homeostasis in RTECs to ensure energy supply for reabsorption functions, but little is known about the alterations in the renal cilium number and length during the progression of DKD. Here, we demonstrate that aberrant ciliogenesis and dramatic increase in the cilium length, the number of ciliated cells, and the length of cilia are positively correlated with the DKD class in the kidney biopsies of DKD patients by super-resolution imaging and appropriate statical analysis methods. This finding was further confirmed in STZ-induced or db/db diabetic mice. These results suggest that the number and length of renal cilia may be clinically relevant indicators and that cilia will be attractive therapeutic targets for DKD.
    Keywords:  ciliotherapy; diabetic kidney disease; primary cilia; renal tubular epithelial cell; therapeutic target
    DOI:  https://doi.org/10.3389/fendo.2022.984452
  5. Metab Brain Dis. 2022 Dec 05.
    H2S-mediated inhibition of RhoA/ROCK pathway and noncoding RNAs in ischemic stroke.
    Weizhuo Lu, Jiyue Wen.
      Ischemic stroke is one of major causes of disability. In the pathological process of ischemic stroke, the up-regulation of Ras homolog gene family, member A (RhoA) and its downstream effector, Ras homolog gene family (Rho)-associated coiled coil-containing kinase (ROCK), contribute to the neuroinflammation, blood-brain barrier (BBB) dysfunction, neuronal apoptosis, axon growth inhibition and astrogliosis. Accumulating evidences have revealed that hydrogen sulphide (H2S) could reduce brain injury in animal model of ischemic stroke via inhibiting the RhoA/ROCK pathway. Recently, noncoding RNAs (ncRNAs) such as circular RNAs (circRNAs), long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have attracted much attention because of their essential role in adjusting gene expression both in physiological and pathological conditions. Numerous studies have uncovered the role of RhoA/ROCK pathway and ncRNAs in ischemic stroke. In this review, we focused on the role of H2S, RhoA/ROCK pathway and ncRNAs in ischemic stroke and aimed to reveal new strategies for preventing and treating this devastating disease.
    Keywords:  H2S; Ischemic stroke; RhoA/ROCK pathway; circRNA; lncRNA; miRNA
    DOI:  https://doi.org/10.1007/s11011-022-01130-1
  6. Pediatr Nephrol. 2022 Dec 06.
    Glomerular hyperfiltration: part 2-clinical significance in children.
    Oyindamola C Adebayo, Agathe B Nkoy, Lambertus P van den Heuvel, Veerle Labarque, Elena Levtchenko, Pierre Delanaye, Hans Pottel.
      Glomerular hyperfiltration (GHF) is a phenomenon that can occur in various clinical conditions affecting the kidneys such as sickle cell disease, diabetes mellitus, autosomal dominant polycystic kidney disease, and solitary functioning kidney. Yet, the pathophysiological mechanisms vary from one disease to another and are not well understood. More so, it has been demonstrated that GHF may occur at the single-nephron in some clinical conditions while in others at the whole-kidney level. In this review, we explore the pathophysiological mechanisms of GHF in relation to various clinical conditions in the pediatric population. In addition, we discuss the role and mechanism of action of important factors such as gender, low birth weight, and race in the pathogenesis of GHF. Finally, in this current review, we further highlight the consequences of GHF in the progression of kidney disease.
    Keywords:  Autosomal dominant polycystic kidney disease (ADPKD); Diabetic kidney disease; Duchenne muscular dystrophy; Glomerular hyperfiltration; Obesity-related glomerulopathy; Pediatric population; Sickle cell disease ; Solitary functioning kidney
    DOI:  https://doi.org/10.1007/s00467-022-05826-5
  7. J Physiol Sci. 2022 Dec 07. 72(1): 32
    Critical role of Rho proteins in myosin light chain di-phosphorylation during early phase of endothelial barrier disruption.
    Mayumi Hirano, Katsuya Hirano.
      We previously reported the Rho-associated coiled-coil containing protein kinase (ROCK)-mediated di-phosphorylation of myosin light chain (MLC) and actin bundle formation at the cell periphery as early events of the endothelial barrier disruption. We herein examined the role of RhoA during early events of barrier disruption. Treatment of cultured porcine aortic endothelial cells with simvastatin prevented the decrease in trans-endothelial electrical resistance, MLC di-phosphorylation and peripheral actin bundle formation seen 3 min after thrombin stimulation. Co-treatment with geranylgeranyl pyrophosphate rescued the thrombin-induced events. Thrombin increased a GTP-bound form of RhoA and phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at the ROCK site. The intracellular introduction of the inhibitory protein of RhoA inhibited the thrombin-induced di-phosphorylation of MLC. However, knockdown of either one of RhoA, RhoB or RhoC failed to inhibit thrombin-induced MLC di-phosphorylation. The findings suggest that Rho proteins play a critical role during early events of thrombin-induced barrier disruption.
    Keywords:  Actin filaments; Barrier function; Myosin light chain; Phosphorylation; Small G protein; Vascular endothelial cells
    DOI:  https://doi.org/10.1186/s12576-022-00857-x
  8. Front Physiol. 2022 ;13 1057200
    Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.
    Auriane C Ernault, Makiri Kawasaki, Benedetta Fabrizi, Pablo Montañés-Agudo, Shirley C M Amersfoorth, Rushd F M Al-Shama, Ruben Coronel, Joris R De Groot.
      Background: Atrial fibrosis plays an important role in the development and persistence of atrial fibrillation by promoting reentry. Primary cilia have been identified as a regulator of fibroblasts (FB) activation and extracellular matrix (ECM) deposition. We hypothesized that selective reduction of primary cilia causes increased fibrosis and facilitates reentry. Aim: The aim of this study was to disrupt the formation of primary cilia in FB and examine its consequences on ECM and conduction in a co-culture system of cardiomyocytes (CM) and FB. Materials: Using short interfering RNA (siRNA), we removed primary cilia in neonatal rat ventricular FB by reducing the expression of Ift88 gene required for ciliary assembly. We co-cultured neonatal rat ventricular cardiomyocytes (CM) with FB previously transfected with Ift88 siRNA (siIft88) or negative control siRNA (siNC) for 48 h. We examined the consequences of ciliated fibroblasts reduction on conduction and tissue remodeling by performing electrical mapping, microelectrode, and gene expression measurements. Results: Transfection of FB with siIft88 resulted in a significant 60% and 30% reduction of relative Ift88 expression in FB and CM-FB co-cultures, respectively, compared to siNC. Knockdown of Ift88 significantly increased the expression of ECM genes Fn1, Col1a1 and Ctgf by 38%, 30% and 18%, respectively, in comparison to transfection with siNC. Conduction velocity (CV) was significantly decreased in the siIft88 group in comparison to siNC [11.12 ± 4.27 cm/s (n = 10) vs. 17.00 ± 6.20 (n = 10) respectively, p < 0.05]. The fraction of sites with interelectrode activation block was larger in the siIft88 group than in the siNC group (6.59 × 10-2 ± 8.01 × 10-2 vs. 1.18 × 10-2 ± 3.72 × 10-2 respectively, p < 0.05). We documented spontaneous reentrant arrhythmias in two cultures in the siIft88 group and in none of the siNC group. Action potentials were not significantly different between siNC and siIft88 groups. Conclusion: Disruption of cilia formation by siIft88 causes ECM remodeling and conduction abnormalities. Prevention of cilia loss could be a target for prevention of arrhythmias.
    Keywords:  atrial fibrillation; cardiac; fibroblasts; fibrosis; primary cilia
    DOI:  https://doi.org/10.3389/fphys.2022.1057200
  9. Cell. 2022 Nov 30. pii: S0092-8674(22)01422-2. [Epub ahead of print]
    IFT-A structure reveals carriages for membrane protein transport into cilia.
    Sophie J Hesketh, Aakash G Mukhopadhyay, Dai Nakamura, Katerina Toropova, Anthony J Roberts.
      Intraflagellar transport (IFT) trains are massive molecular machines that traffic proteins between cilia and the cell body. Each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes, interacts with IFT-B, and uses an array of β-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-A⋅TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK-the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for IFT-A in the train, and shed light on how IFT evolved from a proto-coatomer ancestor.
    Keywords:  AlphaFold; COPI; Cilia; Cryo-EM; G-Protein Coupled Receptor; Intraflagellar Transport; Membrane Protein; Microtubule; Motor Protein; TULP3
    DOI:  https://doi.org/10.1016/j.cell.2022.11.010
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