bims-bicyki 2022-11-27 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–11–27
seventeen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Hereditary thrombotic thrombocytopenic purpura (TTP) with co-occurring autosomal dominant polycystic kidney disease (ADPKD).
The Importance of Radiologic Imaging Modalities in Autosomal Dominant Polycystic Kidney Disease.
Regulation of the PKD2 channel function by TACAN.
Polycystic kidney disease complicates renal pathology in a family with Fabry disease.
Hyperinsulinemic Hypoglycemia Due to PMM2 Mutation in Two Siblings with Autosomal Recessive Polycystic Kidney Disease.
Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.
The tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.
RESET-PKD: A pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease.
Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.
Tissue-specific requirement of sodium channel and clathrin linker 1 (Sclt1) for ciliogenesis during limb development.
Tuning the 3D microenvironment of reprogrammed tubule cells enhances biomimetic modeling of polycystic kidney disease.
The GPCR properties of polycystin-1- A new paradigm.
Composition, organization and mechanisms of the transition zone, a gate for the cilium.
The PGE2/Ptger4b pathway regulates ovulation by inducing intracellular actin cytoskeleton rearrangement via the Rho/Rock pathway in the granulosa cells of periovulatory follicles in the teleost medaka.
Variants in AQP11 may result in autosomal recessive bilateral cystic renal dysgenesis.
Addition of ROCK Inhibitors Alleviates Prostaglandin-Induced Inhibition of Adipogenesis in 3T3L-1 Spheroids.
Assembly and stability of IFT-B complex and its function in BBSome trafficking.

BMJ Case Rep. 2022 Nov 22. pii: e250378. [Epub ahead of print]15(11):

Hereditary thrombotic thrombocytopenic purpura (TTP) with co-occurring autosomal dominant polycystic kidney disease (ADPKD).

Randah Dahlan, Eman Bablghaith.

  Hereditary thrombotic thrombocytopenic purpura (TTP) and autosomal dominant polycystic kidney disease (ADPKD) are two distinct genetic diseases that may affect the kidneys through different mechanisms. ADPKD is a common genetic disorder that leads to exponential formation and growth of cysts replacing all segments of nephrons. Hereditary TTP is a rare autosomal recessive disorder that leads to the disseminated formation of arteriolar platelet-rich thrombi, which produce manifestations of various organs dysfunction. We present a case of a pregnant female with hereditary TTP co-occurring with ADPKD. To our knowledge, this is the first case in the literature describing the co-occurrence of ADPKD and hereditary TTP. We aim to describe the clinical course including the renal and the pregnancy outcomes, describe the consanguinity and family history, and try to explain the potential effect of one disease on the clinical course of the other.

Keywords:  Chronic renal failure; Genetic screening / counselling

DOI:  https://doi.org/10.1136/bcr-2022-250378
Cureus. 2022 Nov;14(11): e31480

The Importance of Radiologic Imaging Modalities in Autosomal Dominant Polycystic Kidney Disease.

Jorge Nadal Bosch, Javier Malcolm, Mario Moya, Michael Menowsky, Paul Dominici.

  Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder that occurs in approximately one in 1000 live births. Patients may be asymptomatic or present with symptoms such as hypertension, hematuria, proteinuria, or renal function impairment. It can present with extra renal complications like cerebral aneurysms, hepatic and pancreatic cysts, infected cysts, cardiac valve disease, colonic diverticula, abdominal wall and inguinal hernia, and seminal vesicle cyst. Imaging studies such as ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) provide vital information regarding the diagnosis of the disease, monitoring of the progression of the disease, and detection of complications from the disease. We present the case of a 40-year-old male who developed extra-renal complications, and how different imaging modalities facilitated and enabled us to optimize the care of this patient in a timely manner.

Keywords:  adpkd; cyst infection; extra-renal manifestation of adpkd; gallium scan; imaging modalities

DOI:  https://doi.org/10.7759/cureus.31480
J Physiol. 2022 Nov 24.

Regulation of the PKD2 channel function by TACAN.

Xiong Liu, Rui Zhang, Mohammad Fatehi, Yifang Wang, Wentong Long, Rui Tian, Xiaoling Deng, Ziyi Weng, Qinyi Xu, Peter E Light, Jingfeng Tang, Xing-Zhen Chen.

   KEY POINTS: TACAN inhibits the PKD2 function in vitro and in vivo. TACAN N-terminal S1-containing fragment T160X interacts with the PKD2 C-terminal fragment N580-L700 while its C-terminal S6-containing fragment L296-D343 interacts with the PKD2 N-terminal A594X. TACAN inhibits the PKD2 channel function through physical interaction. Complex PKD2/TACAN, but not PKD2 alone, confers mechano sensitivity.
ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibits the channel activity of PKD2 gain-of-function mutant F604P. TACAN fragments containing the first and last transmembrane domains interacted with the PKD2 C- and N-terminal fragments, respectively. The TACAN N-terminus acted as a blocking peptide and TACAN inhibited the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single-channel conductance and open probability of PKD2 and mutant F604P. PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we found that TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and would mediate mechano sensitivity of the PKD2/TACAN channel complex. Abstract figure legend PKD2 is a Ca2+ -permeable cation channel and is mutated in about 15% of human autosomal dominant polycystic kidney disease (ADPKD). Using the two-electrode voltage clamp (TEVC) with Xenopus oocytes, patch clamp with mammalian cells, zebrafish model, and molecular biology techniques, we here found that membrane protein TACAN forms a complex with PKD2 on the primary cilia of renal epithelial cell lines and acts as a novel inhibitor of the PKD2 function in vitro and in vivo. This article is protected by copyright. All rights reserved.

Keywords:  ADPKD; CRISPR/Cas9; TMEM120A; Xenopus oocyte; electrophysiology; mammalian cell; mechano sensitivity; zebrafish

DOI:  https://doi.org/10.1113/JP283895
Mol Genet Metab Rep. 2022 Dec;33 100934

Polycystic kidney disease complicates renal pathology in a family with Fabry disease.

Leepakshi Johar, Grace Lee, Angela Martin-Rios, Kathy Hall, Cheng Cheng, Dawn Lombardo, Madeleine Pahl, Virginia Kimonis.

  Fabry disease is a rare lysosomal storage disorder that primarily affects the heart and kidneys, often presenting with reduced renal function. Polycystic kidney disease is a renal condition in which cysts are found, which have a different presentation than the cysts associated with Fabry disease. We report a 60-year-old male patient who was diagnosed with Fabry disease with the classic c.730G > A (p.Asp244Asn) variant of the GLA gene at 34 years of age. Fabry symptoms in this patient include hypohidrosis, hearing loss, corneal whorling, and edema. He also presented with polycystic kidney disease with multiple simple and mildly complex cysts on abdominal ultrasound. Family history of note included Fabry disease in his mother and maternal uncle as well as polycystic kidneys in his mother. Molecular analysis for polycystic kidney disease revealed a variant of uncertain significance (VUS) in the PKD1 gene. Although the in silico studies of this VUS have inconclusive results, the patient fills clinical criteria of autosomal dominant polycystic kidney disease, therefore, Fabry disease and polycystic kidney disease are considered two co-existing manifestations in this family. This case demonstrates the possibility of two renal comorbidities in the same individual and the risk of one diagnosis being overlooked by the other.

Keywords:  Fabry disease; PKD1; Polycystic kidney disease

DOI:  https://doi.org/10.1016/j.ymgmr.2022.100934
Pediatr Rep. 2022 Oct 24. 14(4): 444-449

Hyperinsulinemic Hypoglycemia Due to PMM2 Mutation in Two Siblings with Autosomal Recessive Polycystic Kidney Disease.

Ratna Acharya, Kiran Upadhyay.

  Background: Hyperinsulinemic hypoglycemia (HH) is an important cause of persistent hypoglycemia in newborns and infants. Recently, PMM2 (phosphomannomutase 2) mutation has been associated with HH, especially in conjunction with polycystic kidney disease (PKD). PMM2 deficiency is one of the most common causes of congenital disorder of glycosylation (CDG). Renal involvement in PMM2-CDG manifests as cystic kidney disease, echogenic kidneys, nephrotic syndrome or mild proteinuria. Case Summary: Here, we describe a pair of siblings with HH associated with autosomal recessive polycystic kidney disease (ARPKD) and PMM2 mutation. Two siblings with ARPKD presented during infancy and early toddler years with severe hypoglycemia. Both had inappropriately elevated serum insulin, low β-hydroxybutyrate, a need for a high glucose infusion rate, positive glycemic response to glucagon, positive diazoxide response and PMM2 mutation. Conclusions: Although this combination of HH and PKD was recently described in patients of European descent who also had PMM2 mutation, our report is unique given that these non-consanguineous siblings were not exclusively of European descent. PMM2 mutation leading to abnormal glycosylation and causing cystic kidneys and the alteration of insulin secretion is the most likely pathogenesis of this clinical spectrum.

Keywords:  ARPKD; PMM2; hyperinsulinemia; hypoglycemia

DOI:  https://doi.org/10.3390/pediatric14040052
Nefrologia (Engl Ed). 2022 Nov 17. pii: S2013-2514(22)00121-3. [Epub ahead of print]

Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.

en nombre del grupo de trabajo de Enfermedades Renales Hereditarias de la Sociedad Española de Nefrología

  Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.

Keywords:  ADPKD; Autosomal dominant polycystic kidney disease; Consenso; Consensus; Management; Manejo; PQRAD; Poliquistosis renal autosómica dominante; Progresión; Progression; Recomendaciones; Recommendations

DOI:  https://doi.org/10.1016/j.nefroe.2022.11.011
JCI Insight. 2022 Nov 24. pii: e154773. [Epub ahead of print]

The tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.

Dustin T Nguyen, Emily K Kleczko, Nidhi Dwivedi, Marie-Louise T Monaghan, Berenice Y Gitomer, Michel B Chonchol, Eric T Clambey, Raphael A Nemenoff, Jelena Klawitter, Katharina Hopp.

  Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability exceeding genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through IDO1, are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57Bl/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wildtype. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity as measured by %kidney weight/body weight and cystic index. Consistent with an immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1RC/RC mice and kidney specific Pkd2 knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls with similar changes in the CME as in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a novel therapeutic target for ADPKD.

Keywords:  Amino acid metabolism; Cellular immune response; Monogenic diseases; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.154773
Nephrol Dial Transplant. 2022 Nov 24. pii: gfac311. [Epub ahead of print]

RESET-PKD: A pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease.

Simon Oehm, Konstantin Steinke, Johannes Schmidt, Sita Arjune, Polina Todorova, Christoph Lindemann, Fabian Wöstmann, Franziska Meyer, Florian Siedek, Thomas Weimbs, Roman-Ulrich Müller, Franziska Grundmann.

   BACKGROUND: Ketogenic dietary interventions (KDI) have been shown to be effective in animal models of polycystic kidney disease, but data from clinical trials are lacking.
METHODS: Ten ADPKD patients with rapid disease progression were enrolled at visit V1 and initially maintained a carbohydrate (CHO)-rich diet. At V2, patients entered one of the two KDI arms: a 3-day water fast (WF) or a 14-day ketogenic diet (KD). At V3, they resumed their normal diet for 3 to 6 weeks until V4. At each visit, MRI kidney and liver volumetry was performed. Ketone bodies were evaluated to assess metabolic efficacy and questionnaires were used to determine feasibility.
RESULTS: All participants (KD n = 5, WF n = 5; age 39.8 ± 11.6 years; eGFR 82 ± 23.5 ml/min; total kidney volume (TKV) 2224 ± 1156 ml) were classified as Mayo Class 1C to 1E. Acetone levels in breath and BHB blood levels increased in both study arms (V1 to V2 average acetone: 2.7±1.2 ppm, V2 to V3: 22.8±11.9 ppm, p = 0.0006; V1 to V2 average BHB: 0.22±0.08 mmol/l, V2 to V3: 1.88±0.93 mmol/l, p = 0.0008). 9/10 patients reached a ketogenic state and 9/10 evaluated KDIs as feasible. TKV did not change during this trial. However, we found a significant impact on total liver volume (ΔTLV V2 to V3: -7.7%, p = 0.01), mediated by changes in its non-cystic fraction.
CONCLUSIONS: RESET-PKD demonstrates that short-term KDIs potently induce ketogenesis and are feasible for ADPKD patients in daily life. While TLV quickly changed upon the onset of ketogenesis, changes in TKV may require longer-term interventions.

Keywords:  ADPKD; fasting; ketogenic diet; ketosis; nutrition; polycystic kidney disease

DOI:  https://doi.org/10.1093/ndt/gfac311
Medicina (Kaunas). 2022 Nov 16. pii: 1657. [Epub ahead of print]58(11):

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Othman R Alzahrani, Hanan E Alatwi, Amnah A Alharbi, Abdulrahman H Alessa, Osama M Al-Amer, Abeer F R Alanazi, Anwar M Shams, Esra'a Alomari, Abdallah Y Naser, Faisal A Alzahrani, Salman Hosawi, Saeed M Alghamdi, Wed A Abdali, Imadeldin Elfaki, Yousef M Hawsawi.

  Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein-protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Keywords:  PKD2; autosomal dominant polycystic kidney disease (ADPKD); autosomal recessive polycystic kidney disease (ARPKD); end-stage renal disease ESRD; polycystin-1-polycystin-2 PKD1; whole-exome sequencing

DOI:  https://doi.org/10.3390/medicina58111657
Front Cell Dev Biol. 2022 ;10 1058895

Tissue-specific requirement of sodium channel and clathrin linker 1 (Sclt1) for ciliogenesis during limb development.

Hankyu Lee, Kyeong-Hye Moon, Jieun Song, Suyeon Je, Jinwoong Bok, Hyuk Wan Ko.

  Primary cilia have essential roles as signaling centers during development and adult homeostasis. Disruption of ciliary structure or function causes congenital human disorders called ciliopathies. Centriolar distal appendage (DAP) proteins are important for anchoring cilia to the membrane. However, the exact functions of DAP during in vivo ciliogenesis and animal development remain poorly understood. Here, we showed that the DAP component sodium channel and clathrin linker 1 (Sclt1) mutant mice had abnormal craniofacial and limb development with postnatal lethality. In mutant embryos, most of the affected tissues had defects in DAP recruitment to the basal body and docking to the membrane that resulted in reduced ciliogenesis and disrupted hedgehog (Hh) signaling in limb bud mesenchymal cells. However, limb digit formation and ciliogenesis in Sclt1 mutant mice were differentially affected between the fore- and hindlimb buds. The forelimbs developed normally in Sclt1 mutants, but the hindlimbs had preaxial polydactyly. Heterozygous loss of Cep83, another core DAP component, in Sclt1 mutant mice, caused forelimb and hindlimb polydactyly. These findings revealed the tissue-specific differential requirement of DAPs. Taken together, these results indicated that during limb development the ciliary base components, DAPs, play an essential role in ciliogenesis and Hh signaling in vivo in a position-dependent manner.

Keywords:  SCLT1; ciliogenesis; ciliopathy; distal appendage; limb development; primary cilia

DOI:  https://doi.org/10.3389/fcell.2022.1058895
Biomaterials. 2022 Nov 08. pii: S0142-9612(22)00550-6. [Epub ahead of print]291 121910

Tuning the 3D microenvironment of reprogrammed tubule cells enhances biomimetic modeling of polycystic kidney disease.

Roman Pichler, Ludovica Rizzo, Kevin Tröndle, Michaela Bühler, Hanna Brucker, Anna-Lena Müller, Kelli Grand, Silvia Farè, Amandine Viau, Michael M Kaminski, E Wolfgang Kuehn, Fritz Koch, Stefan Zimmermann, Peter Koltay, Soeren S Lienkamp.

  Renal tubular cells frequently lose differentiation markers and physiological properties when propagated in conventional cell culture conditions. Embedding cells in 3D microenvironments or controlling their 3D assembly by bioprinting can enhance their physiological properties, which is beneficial for modeling diseases in vitro. A potential cellular source for modeling renal tubular physiology and kidney diseases in vitro are directly reprogrammed induced renal tubular epithelial cells (iRECs). iRECs were cultured in various biomaterials and as bioprinted tubular structures. They showed high compatibility with the embedding substrates and dispensing methods. The morphology of multicellular aggregates was substantially influenced by the 3D microenvironment. Transcriptomic analyses revealed signatures of differentially expressed genes specific to each of the selected biomaterials. Using a new cellular model for autosomal-dominant polycystic kidney disease, Pkd1-/- iRECs showed disrupted morphology in bioprinted tubules and a marked upregulation of the Aldehyde dehydrogenase 1a1 (Aldh1a1). In conclusion, 3D microenvironments strongly influence the morphology and expression profiles of iRECs, help to unmask disease phenotypes, and can be adapted to experimental demands. Combining a direct reprogramming approach with appropriate biomaterials will facilitate construction of biomimetic kidney tubules and disease models at the microscale.

Keywords:  Bioprinting; Direct reprogramming; Disease modeling; ECM-Like biomaterials; Kidney tubules; Polycystic kidney disease

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121910
Front Mol Biosci. 2022 ;9 1035507

The GPCR properties of polycystin-1- A new paradigm.

Robin L Maser, James P Calvet, Stephen C Parnell.

  Polycystin-1 (PC1) is an 11-transmembrane (TM) domain-containing protein encoded by the PKD1 gene, the most frequently mutated gene leading to autosomal dominant polycystic kidney disease (ADPKD). This large (> 462 kDal) protein has a complex posttranslational maturation process, with over five proteolytic cleavages having been described, and is found at multiple cellular locations. The initial description of the binding and activation of heterotrimeric Gαi/o by the juxtamembrane region of the PC1 cytosolic C-terminal tail (C-tail) more than 20 years ago opened the door to investigations, and controversies, into PC1's potential function as a novel G protein-coupled receptor (GPCR). Subsequent biochemical and cellular-based assays supported an ability of the PC1 C-tail to bind numerous members of the Gα protein family and to either inhibit or activate G protein-dependent pathways involved in the regulation of ion channel activity, transcription factor activation, and apoptosis. More recent work has demonstrated an essential role for PC1-mediated G protein regulation in preventing kidney cyst development; however, the mechanisms by which PC1 regulates G protein activity continue to be discovered. Similarities between PC1 and the adhesion class of 7-TM GPCRs, most notably a conserved GPCR proteolysis site (GPS) before the first TM domain, which undergoes autocatalyzed proteolytic cleavage, suggest potential mechanisms for PC1-mediated regulation of G protein signaling. This article reviews the evidence supporting GPCR-like functions of PC1 and their relevance to cystic disease, discusses the involvement of GPS cleavage and potential ligands in regulating PC1 GPCR function, and explores potential connections between PC1 GPCR-like activity and regulation of the channel properties of the polycystin receptor-channel complex.

Keywords:  ADPKD; GPS cleavage; heterotrimeric G proteins; polycystin-1; polycystin-2; receptor-ion channel complex; tethered peptide agonist

DOI:  https://doi.org/10.3389/fmolb.2022.1035507
EMBO Rep. 2022 Nov 21. e55420

Composition, organization and mechanisms of the transition zone, a gate for the cilium.

Kwangjin Park, Michel R Leroux.

  The cilium evolved to provide the ancestral eukaryote with the ability to move and sense its environment. Acquiring these functions required the compartmentalization of a dynein-based motility apparatus and signaling proteins within a discrete subcellular organelle contiguous with the cytosol. Here, we explore the potential molecular mechanisms for how the proximal-most region of the cilium, termed transition zone (TZ), acts as a diffusion barrier for both membrane and soluble proteins and helps to ensure ciliary autonomy and homeostasis. These include a unique complement and spatial organization of proteins that span from the microtubule-based axoneme to the ciliary membrane; a protein picket fence; a specialized lipid microdomain; differential membrane curvature and thickness; and lastly, a size-selective molecular sieve. In addition, the TZ must be permissive for, and functionally integrates with, ciliary trafficking systems (including intraflagellar transport) that cross the barrier and make the ciliary compartment dynamic. The quest to understand the TZ continues and promises to not only illuminate essential aspects of human cell signaling, physiology, and development, but also to unravel how TZ dysfunction contributes to ciliopathies that affect multiple organ systems, including eyes, kidney, and brain.

Keywords:  cilia; ciliary gate; ciliary trafficking; ciliopathies; transition zone

DOI:  https://doi.org/10.15252/embr.202255420
Mol Cell Endocrinol. 2022 Nov 18. pii: S0303-7207(22)00264-7. [Epub ahead of print] 111816

The PGE2/Ptger4b pathway regulates ovulation by inducing intracellular actin cytoskeleton rearrangement via the Rho/Rock pathway in the granulosa cells of periovulatory follicles in the teleost medaka.

Katsueki Ogiwara, Chika Fujimori, Takayuki Takahashi.

  We have previously shown that the prostaglandin E2/Ptger4b receptor system is involved in ovulation in teleost medaka and induces intracellular actin cytoskeleton rearrangement in the granulosa cells of preovulatory follicles. In this study, we investigated the signaling pathways through which prostaglandin E2 induces a change in the actin cytoskeleton. Treating preovulatory follicles with GW627368X (Ptger4b antagonist), a Rho inhibitor, or Y-27632 [Rho-associated protein kinase (Rock) inhibitor] inhibited not only in vitro follicle ovulation but also intracellular actin cytoskeleton rearrangement. Active Rhoa-c and Rock1 were detected in follicles immediately before ovulation. GW627368X also inhibited Rhoa-c activation and cytoskeleton rearrangement. PGE2-induced actin cytoskeleton rearrangement was not observed in the Ptger4b-, Rhoa-c-, or Rock1-deficient OLHNI-2 cells. These results indicate that the PGE2/Ptger4b pathway regulates intracellular actin cytoskeleton rearrangement via the Rho/Rock pathway in the granulosa cells of preovulatory follicles during medaka ovulation.

Keywords:  Intracellular actin cytoskeleton rearrangement; Medaka ovulation; PGE(2); Ptger4b; Rho; Rock

DOI:  https://doi.org/10.1016/j.mce.2022.111816
Am J Med Genet A. 2022 Nov 24.

Variants in AQP11 may result in autosomal recessive bilateral cystic renal dysgenesis.

Michael E Price, Kristen P Fishler, Melissa Muff-Luett, Teri J Mauch, Luca Brunelli, Joshua C Euteneuer.

  Congenital renal cystic dysplasia is a rare disease that occurs in approximately 1 in 4000 children and is often discovered in the antenatal period by ultrasound. It is commonly associated with oligohydramnios in utero and/or renal insufficiency or failure in the postnatal period. Aquaporins are membrane proteins that serve as transport channels in the transfer of water or small solutes across cell membranes. They play a role in the development of renal cysts. Aquaporin 11 (AQP11) deficient mice develop polycystic kidney disease in utero due to disruption of polycystin-1. Here we describe a case of bilateral cystic kidney disease in a patient with novel compound heterozygous variants in AQP11: c.780G>T (p. Trp260Cys) and c.472C>T (p.Pro158Ser) (NM_173039.2) identified by whole genome sequencing. These findings suggest, for the first time, the potential role of AQP11 in congenital renal cystic dysplasia.

Keywords:  AQP11; NICU; polycystic kidney disease; renal dysplasia

DOI:  https://doi.org/10.1002/ajmg.a.63056
Bioengineering (Basel). 2022 Nov 17. pii: 702. [Epub ahead of print]9(11):

Addition of ROCK Inhibitors Alleviates Prostaglandin-Induced Inhibition of Adipogenesis in 3T3L-1 Spheroids.

Yosuke Ida, Tatsuya Sato, Araya Umetsu, Megumi Watanabe, Masato Furuhashi, Fumihito Hikage, Hiroshi Ohguro.

  To elucidate the additive effects of the ROCK inhibitors (ROCK-i), ripasudil (Rip) and Y27632 on bimatoprost acid (BIM-A), a prostaglandin analog (PG), on adipose tissue, two- and three-dimensional (2D or 3D) cultures of 3T3-L1 cells, the most well characterized cells in the field of lipid research, were used. The cells were subjected to a variety of analyses including lipid staining, real-time cellular metabolic analysis, the mRNA expressions of genes related to adipogenesis and extracellular matrices (ECMs) as well as the sizes and physical properties of the 3D spheroids by a micro-squeezer. BIM-A induced strong inhibitory effects on most of the adipogenesis-related changes in the 2D and 3D cultured 3T3-L1 cells, including (1) the enlargement and softening of the 3D spheroids, (2) a dramatic enhancement in lipid staining and the expression of adipogenesis-related genes, and (3) a decrease in mitochondrial and glycolytic metabolic function. By adding ROCK-i to the BIM-A, most of these BIM-A-induced effects were cancelled. The collective findings reported herein suggest that ROCK-i eliminated the PG-induced suppression of adipogenesis in the 3T3-L1 cells, accompanied by the formation of enlarged 3D spheroids. Such effects of adding ROCK-i to a PG in preadipocytes on cellular properties appear to be associated with the suppression of PG-induced adverse effects, and provide additional insight into our understanding of lipid-related research.

Keywords:  3-dimensional (3D) tissue culture; 3T3-L1 cell; ROCK; ROCK inhibitor; Rho-kinase; upper eyelid sulcus (DUES) deepening

DOI:  https://doi.org/10.3390/bioengineering9110702
iScience. 2022 Dec 22. 25(12): 105493

Assembly and stability of IFT-B complex and its function in BBSome trafficking.

Jieling Wang, Xin Zhu, Zhengmao Wang, Xuecheng Li, Hui Tao, Junmin Pan.

  The machinery of intraflagellar transport (IFT) consists of IFT motors and the ciliary cargo adaptors including IFT-A and IFT-B complexes and BBSome. IFT-B, which is composed of IFT-B1 and IFT-B2 subcomplexes, interacts with IFT motors and IFT-A during anterograde IFT and IFT-A during retrograde IFT while it is also implicated in BBSome trafficking. However, the assembly and stability of IFT-B and its regulation of anterograde IFT and BBSome trafficking remain not clear. Here, we show that IFT38 functions in the regulation of anterograde IFT and retrograde trafficking of BBSome. Deletion of IFT-B1 or IFT-B2 subunits results in differential instability of IFT-B1 and IFT-B2. The stability of IFT-B1 and IFT-B2 is mutually dependent and mediated by the connecting tetramer IFT38/5788/52. The formation of an intact IFT-B1 and IFT-B2 is not altered by the deletion of IFT38 of IFT-B2 and IFT52 of IFT-B1, respectively. Further analysis suggests a modular pathway for IFT-B assembly.

Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2022.105493