bims-bicyki 2023-04-09 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2023–04–09
twenty papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Editorial: Signaling by primary cilia in development and disease.
Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.
Autosomal dominant and autosomal recessive polycystic kidney disease: hypertension and secondary cardiovascular effect in children.
The actin-bundling protein Fascin-1 modulates ciliary signalling.
Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.
Novel multi-allelic variants, two BBS2 and one PKD1 variant, of renal ciliopathies: A case report and literature review.
Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.
Cholesterol in the ciliary membrane as a therapeutic target against cancer.
Chondrocyte primary cilia lengthening and shortening in response to mediators of osteoarthritis; a role for integrin α1β1 and focal adhesions.
Calcium signaling in polycystic kidney disease- cell death and survival.
Computational study of biomechanical drivers of renal cystogenesis.
The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2.
The ancestral ESCRT protein TOM1L2 selects ubiquitinated cargoes for retrieval from cilia.
Calcineurin associates with centrosomes and regulates cilia length maintenance.
A stress-induced cilium-to-PML-NB route drives senescence initiation.
Ciliopathies in pediatric endocrinology.
Shift from severe hypotension to salt-dependent hypertension in a child with autosomal recessive polycystic kidney disease after bilateral nephrectomies: a case report.
Congenital abnormalities of heart and kidney.
Unroofing of Lower Pole Native Kidney Cysts in Patients with Autosomal Dominant Polycystic Kidneys at the Time of Kidney Transplantation.
Title: Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain.

Front Cell Dev Biol. 2023 ;11 1186367

Editorial: Signaling by primary cilia in development and disease.

Sung-Eun Kim, Inna Nechipurenko, Søren Tvorup Christensen.



Keywords:  ciliary genes; ciliogenesis; ciliopathy; primary cilia; signaling pathways

DOI:  https://doi.org/10.3389/fcell.2023.1186367
Physiol Rep. 2023 Apr;11(7): e15652

Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease.

Sergey N Arkhipov, D'Anna L Potter, Regina F Sultanova, Daria V Ilatovskaya, Peter C Harris, Tengis S Pavlov.

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1RC/RC mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1RC/RC and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1RC/RC mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCDcl4 cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCDcl4 epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology.

DOI: https://doi.org/10.14814/phy2.15652
Front Mol Biosci. 2023 ;10 1112727

Autosomal dominant and autosomal recessive polycystic kidney disease: hypertension and secondary cardiovascular effect in children.

L Lucchetti, M Chinali, F Emma, L Massella.

  Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are the most widely known cystic kidney diseases. They are significantly different from each other in terms of genetics and clinical manifestations. Hypertension is one of the main symptoms in both diseases, but the age of onset and secondary cardiovascular complications are significantly different. Most ARPKD children are hypertensive in the first year of life and need high doses of hypertensive drugs. ADPKD patients with a very early onset of the disease (VEOADPKD) develop hypertension similarly to patients with ARPKD. Conversely, a significantly lower percentage of patients with classic forms of ADPKD develops hypertension during childhood, although probably more than originally thought. Data published in the past decades show that about 20%-30% of ADPKD children are hypertensive. Development of hypertension before 35 years of age is a known risk factor for more severe disease in adulthood. The consequences of hypertension on cardiac geometry and function are not well documented in ARPKD due to the rarity of the disease, the difficulties in collecting homogeneous data, and differences in the type of parameters evaluated in different studies. Overall, left ventricular hypertrophy (LVH) has been reported in 20%-30% of patients and does not always correlate with hypertension. Conversely, cardiac geometry and cardiac function are preserved in the vast majority of hypertensive ADPKD children, even in patients with faster decline of kidney function. This is probably related to delayed onset of hypertension in ADPKD, compared to ARPKD. Systematic screening of hypertension and monitoring secondary cardiovascular damage during childhood allows initiating and adapting antihypertensive treatment early in the course of the disease, and may limit disease burden later in adulthood.

Keywords:  ADPKD; ARPKD; cardiovascular disease; children; hypertension

DOI:  https://doi.org/10.3389/fmolb.2023.1112727
J Mol Cell Biol. 2023 Apr 04. pii: mjad022. [Epub ahead of print]

The actin-bundling protein Fascin-1 modulates ciliary signalling.

Lena Brücker, Stefanie Kornelia Becker, Vanessa Maissl, Gregory Harms, Maddy Parsons, Helen Louise May-Simera.

  Primary cilia are microtubule-based cell organelles important for cellular communication. Since they are involved in the regulation of numerous signalling pathways, defects in cilia development or function are associated with genetic disorders, collectively called ciliopathies. Besides their ciliary functions, recent research has shown that several ciliary proteins are involved in the coordination of the actin cytoskeleton. Although ciliary and actin phenotypes are related, the exact nature of their interconnection remains incompletely understood. Here we show that the protein BBS6, associated with the ciliopathy Bardet-Biedl syndrome, cooperates with the actin-bundling protein Fascin-1 in regulating filopodia and ciliary signalling. We found that loss of Bbs6 affects filopodia length potentially via attenuated interaction with Fascin-1. Conversely, loss of Fascin-1 leads to a ciliary phenotype, subsequently affecting ciliary Wnt signalling, possibly in collaboration with BBS6. Our data shed light on how ciliary proteins are involved in actin regulations and provide new insight into the involvement of the actin regulator Fascin-1 in ciliogenesis and cilia-associated signalling. Advancing our knowledge of the complex regulations between primary cilia and actin dynamics is important to understand the pathogenic consequences of ciliopathies.

Keywords:  actin; bardet–biedl syndrome; cilia; ciliopathy; filopodia; signalling; wnt

DOI:  https://doi.org/10.1093/jmcb/mjad022
J Biomol Struct Dyn. 2023 Apr 08. 1-18

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.

Mojgan Nejabat, Farzin Hadizadeh, Masoud Nejabat, Omid Rajabi.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.

Keywords:  ADPKD; Autosomal dominant polycystic kidney disease; MD simulation; ZINC; molecular docking; natural products; sesquiterpene coumarins

DOI:  https://doi.org/10.1080/07391102.2023.2196700
Eur J Med Genet. 2023 Mar 30. pii: S1769-7212(23)00059-9. [Epub ahead of print] 104753

Novel multi-allelic variants, two BBS2 and one PKD1 variant, of renal ciliopathies: A case report and literature review.

Fazhan Zhong, Mei Tan, Yan Gao.

   BACKGROUND: Bardet-Biedl syndrome (BBS) and autosomal dominant polycystic kidney disease (ADPKD) are renal ciliopathies. BBS has 22 pathogenic genes, and ADPKD is mainly caused by PKD1 and PKD2 variants. Cases with tri-allelic variants of BBS and PKD1 are rare.
CASE PRESENTATION: The proband was an 11-year-old Chinese male with cysts in both kidneys, blurred vision, hyperopia, and short fingers and toes. The patient underwent a kidney transplant due to rapid deterioration of renal failure. During follow-up, a smaller field of vision, a slow increase in height, and a weight gain were observed. In addition, renal function and anemia were improved. High-throughput sequencing analysis showed two heterozygous variants in BBS2 (c.563delT (p.I188Tfs*13) inherited from the father and c.534+1G > t (splicing) from the mother) and one heterozygous variant in PKD1 (c.6223C > T (p.R2075C)) inherited from the mother.
CONCLUSION: This paper reported a ciliopathy patient with multi-allelic variants (two BBS2 variants and one PKD1 variant) that may lead to early symptoms and more rapid progression. An early genetic diagnosis may contribute to predicting disease progression and guiding management and follow-up.

Keywords:  Autosomal dominant; Bardet-Biedl syndrome; Case report; Ciliopathies; Polycystic kidney

DOI:  https://doi.org/10.1016/j.ejmg.2023.104753
Eur Radiol. 2023 Apr 05.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

Anna Caroli, Giulia Villa, Paolo Brambilla, Matias Trillini, Kanishka Sharma, Sandro Sironi, Giuseppe Remuzzi, Norberto Perico, Andrea Remuzzi.

   OBJECTIVES: Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure.
METHODS: T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5 T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed.
RESULTS: There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007).
CONCLUSIONS: DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion.
CLINICAL RELEVANCE STATEMENT: This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion.
KEY POINTS: • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

Keywords:  Cysts; Diffusion magnetic resonance imaging; Fibrosis; Polycystic kidney diseases; Polycystic kidney, autosomal dominant

DOI:  https://doi.org/10.1007/s00330-023-09601-4
Front Mol Biosci. 2023 ;10 1160415

Cholesterol in the ciliary membrane as a therapeutic target against cancer.

Sotai Kimura, Tomoka Morita, Kosuke Hosoba, Hiroshi Itoh, Takashi Yamamoto, Tatsuo Miyamoto.

  Primary cilium is a non-motile, antenna-like structure that develops in the quiescent G0 phase-cell surface. It is composed of an array of axonemal microtubules polymerized from the centrosome/basal body. The plasma membrane surrounding the primary cilium, which is called the ciliary membrane, contains a variety of receptors and ion channels, through which the cell receives extracellular chemical and physical stimuli to initiate signal transduction. In general, primary cilia disappear when cells receive the proliferative signals to re-enter the cell cycle. Primary cilia thus cannot be identified in many malignant and proliferative tumors. In contrast, some cancers, including basal cell carcinoma, medulloblastoma, gastrointestinal stromal tumor, and other malignancies, retain their primary cilia. Importantly, it has been reported that the primary cilia-mediated oncogenic signals of Hedgehog, Wnt, and Aurora kinase A are involved in the tumorigenesis and tumor progression of basal cell carcinoma and some types of medulloblastoma. It has also been demonstrated that cholesterol is significantly more enriched in the ciliary membrane than in the rest of the plasma membrane to ensure Sonic hedgehog signaling. A series of epidemiological studies on statin drugs (cholesterol-lowering medication) demonstrated that they prevent recurrence in a wide range of cancers. Taken together, ciliary cholesterol could be a potential therapeutic target in primary cilia-dependent progressive cancers.

Keywords:  Wnt signal; cancers; cholesterol; primary cilia; sonic hedgehog signal

DOI:  https://doi.org/10.3389/fmolb.2023.1160415
Osteoarthr Cartil Open. 2023 Jun;5(2): 100357

Chondrocyte primary cilia lengthening and shortening in response to mediators of osteoarthritis; a role for integrin α1β1 and focal adhesions.

Lauren B Stam, Andrea L Clark.

   Objective: Integrin α1β1 protects against osteoarthritis when it is upregulated in the early stages of disease, however, the mechanism behind this is currently unknown. Hypo-osmotic stress, interleukin-1 (IL-1) and transforming growth factor β (TGFβ) influence chondrocyte signaling and are important mediators of osteoarthritis. Evidence for primary cilia as a signaling hub for these factors and the involvement of the F-actin cytoskeleton in this response is growing. The purpose of this study was to investigate the role of integrin α1β1 in the response of primary cilia and the F-actin cytoskeleton to these osteoarthritic mediators.
Design: Primary cilia length and the number of F-actin peaks were measured in ex vivo wild type and itga1-null chondrocytes in response to hypo-osmotic stress, IL-1, and TGFβ alone or in combination, and with or without focal adhesion kinase inhibitor.
Results: We show that integrin α1β1 and focal adhesions are necessary for cilial lengthening and increases in F-actin peaks with hypo-osmotic stress and IL-1, but are not required for cilial shortening with TGFβ. Furthermore, we established that the chondrocyte primary cilium has a resting length of 2.4 μm, a minimum length of 2.1 μm corresponding to the thickness of the pericellular matrix, and a maximum length of 3.0 μm.
Conclusions: While integrin α1β1 is not necessary for the formation of chondrocyte primary cilia and cilial shortening in response to TGFβ, it is necessary for the mediation of cilial lengthening and the formation of F-actin peaks in response to hypo-osmotic stress and IL-1.

Keywords:  Chondrocyte; F-actin; Integrins; Osteoarthritis; Primary cilia

DOI:  https://doi.org/10.1016/j.ocarto.2023.100357
Cell Calcium. 2023 Mar 31. pii: S0143-4160(23)00045-3. [Epub ahead of print]112 102733

Calcium signaling in polycystic kidney disease- cell death and survival.

Karla M Márquez-Nogueras, Virdjinija Vuchkovska, Ivana Y Kuo.

  Polycystic kidney disease is typified by cysts in the kidney and extra-renal manifestations including hypertension and heart failure. The main genetic underpinning this disease are loss-of function mutations to the two polycystin proteins, polycystin 1 and polycystin 2. Molecularly, the disease is characterized by changes in multiple signaling pathways including down regulation of calcium signaling, which, in part, is contributed by the calcium permeant properties of polycystin 2. These signaling pathways enable the cystic cells to survive and avoid cell death. This review focuses on the studies that have emerged in the past 5 years describing how the structural insights gained from PC-1 and PC-2 inform the calcium dependent molecular pathways of autophagy and the unfolded protein response that are regulated by the polycystin proteins and how it leads to cell survival and/or cell death.

Keywords:  ADPKD; Autophagy; Cell survival; Kidney cysts; TRP channels

DOI:  https://doi.org/10.1016/j.ceca.2023.102733
Biomech Model Mechanobiol. 2023 Apr 06.

Computational study of biomechanical drivers of renal cystogenesis.

Gerard A Ateshian, Katherine A Spack, James C Hone, Evren U Azeloglu, G Luca Gusella.

  Renal cystogenesis is the pathological hallmark of autosomal dominant polycystic kidney disease, caused by PKD1 and PKD2 mutations. The formation of renal cysts is a common manifestation in ciliopathies, a group of syndromic disorders caused by mutation of proteins involved in the assembly and function of the primary cilium. Cystogenesis is caused by the derailment of the renal tubular architecture and tissue deformation that eventually leads to the impairment of kidney function. However, the biomechanical imbalance of cytoskeletal forces that are altered in cells with Pkd1 mutations has never been investigated, and its nature and extent remain unknown. In this computational study, we explored the feasibility of various biomechanical drivers of renal cystogenesis by examining several hypothetical mechanisms that may promote morphogenetic markers of cystogenesis. Our objective was to provide physics-based guidance for our formulation of hypotheses and our design of experimental studies investigating the role of biomechanical disequilibrium in cystogenesis. We employed the finite element method to explore the role of (1) wild-type versus mutant cell elastic modulus; (2) contractile stress magnitude in mutant cells; (3) localization and orientation of contractile stress in mutant cells; and (4) sequence of cell contraction and cell proliferation. Our objective was to identify the factors that produce the characteristic tubular cystic growth. Results showed that cystogenesis occurred only when mutant cells contracted along the apical-basal axis, followed or accompanied by cell proliferation, as long as mutant cells had comparable or lower elastic modulus than wild-type cells, with their contractile stresses being significantly greater than their modulus. Results of these simulations allow us to focus future in vitro and in vivo experimental studies on these factors, helping us formulate physics-based hypotheses for renal tubule cystogenesis.

Keywords:  Cystogenesis; Finite element modeling; Growth and remodeling; Polycystic kidney disease

DOI:  https://doi.org/10.1007/s10237-023-01704-7
J Biol Chem. 2023 Apr 05. pii: S0021-9258(23)00316-2. [Epub ahead of print] 104674

The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2.

Yan Wang, Zhifei Wang, Mahmud Arif Pavel, Courtney Ng, Parul Kashyap, Bin Li, Tiago D C Morais, Gabriella A Ulloa, Yong Yu.

  Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes. The latter encodes polycystin-2 (PC2, also known as TRPP2), a member of the transient receptor potential (TRP) ion channel family. Despite most pathogenic mutations in PKD2 being truncation variants, there are also many point mutations, which cause small changes in protein sequences but dramatic changes in the in vivo function of PC2. How these mutations affect PC2 ion channel function is largely unknown. In this study, we systematically tested the effects of 31 point mutations on the ion channel activity of a gain-of-function PC2 mutant, PC2_F604P, expressed in Xenopus oocytes. The results show that all mutations in the transmembrane domains and channel pore region, and most mutations in the extracellular TOP domain, are critical for PC2_F604P channel function. In contrast, the other mutations in the TOP domain and most mutations in the C-terminal tail cause mild or no effects on channel function as assessed in Xenopus oocytes. To understand the mechanism of these effects, we have discussed possible conformational consequences of these mutations based on the cryo-EM structures of PC2. The results help gain insight into the structure and function of the PC2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.

Keywords:  gain-of-function; genetic disease; ion channel; kidney; mutant; polycystin-2; protein structure; transient receptor potential channels (TRP channels)

DOI:  https://doi.org/10.1016/j.jbc.2023.104674
Dev Cell. 2023 Mar 29. pii: S1534-5807(23)00099-0. [Epub ahead of print]

The ancestral ESCRT protein TOM1L2 selects ubiquitinated cargoes for retrieval from cilia.

Swapnil Rohidas Shinde, David U Mick, Erika Aoki, Rachel B Rodrigues, Steven P Gygi, Maxence V Nachury.

  Many G protein-coupled receptors (GPCRs) reside within cilia of mammalian cells and must undergo regulated exit from cilia for the appropriate transduction of signals such as hedgehog morphogens. Lysine 63-linked ubiquitin (UbK63) chains mark GPCRs for regulated removal from cilia, but the molecular basis of UbK63 recognition inside cilia remains elusive. Here, we show that the BBSome-the trafficking complex in charge of retrieving GPCRs from cilia-engages the ancestral endosomal sorting factor target of Myb1-like 2 (TOM1L2) to recognize UbK63 chains within cilia of human and mouse cells. TOM1L2 directly binds to UbK63 chains and the BBSome, and targeted disruption of the TOM1L2/BBSome interaction results in the accumulation of TOM1L2, ubiquitin, and the GPCRs SSTR3, Smoothened, and GPR161 inside cilia. Furthermore, the single-cell alga Chlamydomonas also requires its TOM1L2 ortholog in order to clear ubiquitinated proteins from cilia. We conclude that TOM1L2 broadly enables the retrieval of UbK63-tagged proteins by the ciliary trafficking machinery.

Keywords:  BBSome; ESCRT; GPCR; cilia; ubiquitin

DOI:  https://doi.org/10.1016/j.devcel.2023.03.003
J Cell Sci. 2023 Apr 03. pii: jcs.260353. [Epub ahead of print]

Calcineurin associates with centrosomes and regulates cilia length maintenance.

Eirini Tsekitsidou, Cassandra J Wong, Idil Ulengin-Talkish, Angela I M Barth, Tim Stearns, Anne-Claude Gingras, Jennifer T Wang, Martha S Cyert.

  Calcineurin, or PP2B, the Ca2+ and calmodulin-activated phosphatase and target of immunosuppressants, has many substrates and functions that remain undiscovered. By combining rapid proximity-dependent labeling with cell cycle synchronization, we mapped the spatial distribution of calcineurin in different cell cycle stages. While calcineurin-proximal proteins did not vary significantly between interphase and mitosis, calcineurin consistently associated with multiple centrosomal/ciliary proteins. These include POC5, which binds centrin in a Ca2+-dependent manner and is a component of the luminal scaffold that stabilizes centrioles. We show that POC5 contains a calcineurin substrate motif (PxIxIT-type) that mediates calcineurin binding in vivo and in vitro. Using indirect immunofluorescence and ultrastructure expansion microscopy, we demonstrate that calcineurin co-localizes with POC5 at the centriole, and further show that calcineurin inhibitors alter POC5 distribution within the centriole lumen. Our discovery that calcineurin directly associates with centriolar proteins highlights a role for Ca2+ and calcineurin signaling at these organelles. Calcineurin inhibition promotes primary cilia elongation without affecting ciliogenesis. Thus, Ca2+ signaling within cilia includes previously unknown functions for calcineurin in cilia length maintenance, a process frequently disrupted in ciliopathies.

Keywords:  Calcineurin; Centriole; Centrosome; Cilia; POC5; Phosphatase

DOI:  https://doi.org/10.1242/jcs.260353
Nat Commun. 2023 Apr 03. 14(1): 1840

A stress-induced cilium-to-PML-NB route drives senescence initiation.

Xiaoyu Ma, Yingyi Zhang, Yuanyuan Zhang, Xu Zhang, Yan Huang, Kai He, Chuan Chen, Jielu Hao, Debiao Zhao, Nathan K LeBrasseur, James L Kirkland, Eduardo N Chini, Qing Wei, Kun Ling, Jinghua Hu.

Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in stressed cells remains vague. Here, we discover that exposure to irradiation, oxidative or inflammatory stressors induces transient biogenesis of primary cilia, which are then used by stressed cells to communicate with the promyelocytic leukemia nuclear bodies (PML-NBs) to initiate senescence responses in human cells. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs and release UBC9 to SUMOylate FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB biogenesis and PML-NB-dependent senescence initiation. Remarkably, Fbf1 ablation effectively subdues global senescence burden and prevents associated health decline in irradiation-treated mice. Collectively, our findings assign the primary cilium a key role in senescence induction in mammalian cells and, also, a promising target in future senotherapy strategies.

DOI: https://doi.org/10.1038/s41467-023-37362-7
Ann Pediatr Endocrinol Metab. 2023 Mar;28(1): 5-9

Ciliopathies in pediatric endocrinology.

Ilenia Cicolini, Annalisa Blasetti, Francesco Chiarelli.

  Ciliopathies are a group of disorders that involve many organs and systems. In this review, we consider the role of the cilium in multiorgan pathology with a focus on endocrinological aspects. Identification of new genes and mutations is the major challenge in development of a tailored and appropriate therapy. It is expected that new mutations will be identified to characterize ciliopathies and promote new therapies.

Keywords:  Cilia; Ciliopathies; Signaling

DOI:  https://doi.org/10.6065/apem.2244288.144
BMC Nephrol. 2023 04 04. 24(1): 86

Shift from severe hypotension to salt-dependent hypertension in a child with autosomal recessive polycystic kidney disease after bilateral nephrectomies: a case report.

Dovile Ruzgiene, Lauryna Abraityte, Karolis Azukaitis, Max Christoph Liebau, Augustina Jankauskiene.

   BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a significant cause of morbidity and mortality in infants and children. In severe cases bilateral nephrectomies are considered but may be associated with significant neurological complications and life-threatening hypotension.
CASE PRESENTATION: We describe a case of a 17 months old boy with genetically confirmed ARPKD who underwent sequential bilateral nephrectomies at the age of 4 and 10 months. Following the second nephrectomy the boy was started on continuous cycling peritoneal dialysis with blood pressure on the lower range. At the age of 12 months after a few days of poor feeding at home the boy experienced a severe episode of hypotension and coma of Glasgow Come Scale of three. Brain magnetic-resonance imaging (MRI) showed signs of hemorrhage, cytotoxic cerebral edema and diffuse cerebral atrophy. During the subsequent 72 h he developed seizures requiring anti-epileptic drug therapy, gradually regained consciousness but remained significantly hypotensive after discontinuation of vasopressors. Thus, he received high doses of sodium chloride orally and intraperitoneally as well as midodrine hydrochloride. His ultrafiltration (UF) was targeted to keep him in mild-to-moderate fluid overload. After two months of stable condition the patient started to develop hypertension requiring four antihypertensive medications. After optimizing peritoneal dialysis to avoid fluid overload and discontinuation of sodium chloride the antihypertensives were discontinued, but hyponatremia with hypotensive episodes reoccurred. Sodium chloride was reintroduced resulting in recurrent salt-dependent hypertension.
CONCLUSIONS: Our case report illustrates an unusual course of blood pressure changes following bilateral nephrectomies in an infant with ARPKD and the particular importance of tight regulation of sodium chloride supplementation. The case adds to the scarce literature about clinical sequences of bilateral nephrectomies in infants, and as well highlights the challenge of managing blood pressure in these patients. Further research on the mechanisms and management of blood pressure control is clearly needed.

Keywords:  Autosomal recessive polycystic kidney disease; Bilateral nephrectomy; Children; Hypertension; Hypotension

DOI:  https://doi.org/10.1186/s12882-023-03140-2
Clin Case Rep. 2023 Apr;11(4): e7158

Congenital abnormalities of heart and kidney.

Hiroya Takafuji, Nahoko Kato, Yuta Azumi, Kotaro Obunai.

  Patients with congenital anomalies of the kidney and urinary tract (CAKUT) may be at risk for congenital cardiac defects or cardiomyopathies as comorbidities. It is crucial to recognize the coexistence of cardiac abnormalities and CAKUT and recommend screening for cardiac involvement in CAKUT patients using echocardiography.

Keywords:  atrial septal defect; autosomal dominant polycystic kidney disease; hemodialysis; left ventricular hypertrophy

DOI:  https://doi.org/10.1002/ccr3.7158
Urol J. 2023 Apr 03.

Unroofing of Lower Pole Native Kidney Cysts in Patients with Autosomal Dominant Polycystic Kidneys at the Time of Kidney Transplantation.

Abbas Basiri, Nasser Simforoosh, Amirhossein Nayebzade, Hamed Marufi, Amir Hossein Kashi.

To report our experience with unroofing of ipsilateral lower pole kidney cysts in five patients with adult-type polycystic kidneys [ADPKD] when free implantation of kidney allograft interfered with lower pole native kidney cysts. In all of these patients, the native kidneys extended to the ipsilateral pelvis and bilateral ADPKD caused enlargement of the abdomen on gross examination. Unroofing of lower pole kidney cysts was performed during the same session of allograft transplantation. The decision to unroof lower pole cysts of the ipsilateral kidney was made after observing interference of lower pole cysts with free implantation of the allograft. In patient A, bilateral native nephrectomy was performed 6 weeks after kidney transplantation after consultation with the patient, when there was evidence of the good function of the allograft and the recipient was on a low dose of immunosuppressive medications. In other patients, no need for native nephrectomy observed. This experience suggests the possibility that when large ipsilateral kidney cysts interfere with safe implantation of the allograft, there is an option of performing cyst unroofing at the same session and proceeding with allograft implantation. In many patients, there would be no need for native nephrectomy and of deemed necessary, it will be performed later, when there is evidence of the good function of the allograft and the patient is on good kidney function with a low dose of immunosuppressive medications and a less risk profile for the operation. To our best knowledge, there is no prior such report in the literature.

DOI: https://doi.org/10.22037/uj.v20i.7047
Mol Ther. 2023 Apr 03. pii: S1525-0016(23)00163-6. [Epub ahead of print]

Title: Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain.

Rong Ma, Naseer A Kutchy, Zhongbin Wang, Guoku Hu.

Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.

DOI: https://doi.org/10.1016/j.ymthe.2023.03.030