bims-bicyki 2021-02-28 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2021–02–28
ten papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Role of the Polycystins as Mechanosensors of Extracellular Stiffness.
Diagnostic accuracy of administrative codes for autosomal dominant polycystic kidney disease in clinic patients with cystic kidney disease.
Primary Cilia and Atherosclerosis.
Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone.
Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1.
Characterization of early postzygotic somatic mutations through multi-organ analysis.
[Clinical use of tolvaptan: a 2021 review].
Piezo1 regulates intestinal epithelial function by affecting the tight junction protein claudin-1 via the ROCK pathway.
Extracellular matrix density regulates the formation of tumour spheroids through cell migration.
Wnt/β-catenin signaling: structure, assembly and endocytosis of the signalosome.

Am J Physiol Renal Physiol. 2021 Feb 22.

Role of the Polycystins as Mechanosensors of Extracellular Stiffness.

Elisa A Nigro, Alessandra Boletta.

  Polycystin-1 (PC-1) is a transmembrane protein, encoded by the PKD1 gene, mutated in Autosomal Dominant Polycystic Kidney Disease (ADPKD). This common genetic disorder, characterized by cyst formation in both kidneys, ultimately leading to renal failure, is still waiting for a definitive treatment. The overall function of PC-1 and the molecular mechanism responsible for cyst formation are slowly coming to light, but they are both still intensively studied. In particular, PC-1 has been proposed to act as a mechanosensor, although the precise signal that activates the mechanical properties of this protein has been long debated and questioned. In this Review we report studies and evidences of PC-1 function as a mechanosensor, starting from the peculiarity of its structure, through the long journey that progressively shed new light on the potential initiating events of cystogenesis, concluding with the description of PC-1 recently shown ability to sense the mechanical stimuli provided by the stiffness of the extracellular environment. These new findings have potentially important implications for the understanding of ADPKD pathophysiology and potentially for designing new therapies.

Keywords:  cysts; mechanosensation; polycystic kidney disease

DOI:  https://doi.org/10.1152/ajprenal.00545.2020
Clin Kidney J. 2021 Feb;14(2): 612-616

Diagnostic accuracy of administrative codes for autosomal dominant polycystic kidney disease in clinic patients with cystic kidney disease.

Vinusha Kalatharan, Eric McArthur, Danielle M Nash, Blayne Welk, Sisira Sarma, Amit X Garg, York Pei.

   Background: The ability to identify patients with autosomal dominant polycystic kidney disease (ADPKD) and distinguish them from patients with similar conditions in healthcare administrative databases is uncertain. We aimed to measure the sensitivity and specificity of different ADPKD administrative coding algorithms in a clinic population with non-ADPKD and ADPKD kidney cystic disease.
Methods: We used a dataset of all patients who attended a hereditary kidney disease clinic in Toronto, Ontario, Canada between 1 January 2010 and 23 December 2014. This dataset included patients who met our reference standard definition of ADPKD or other cystic kidney disease. We linked this dataset to healthcare databases in Ontario. We developed eight algorithms to identify ADPKD using the International Classification of Diseases, 10th Revision (ICD-10) codes and provincial diagnostic billing codes. A patient was considered algorithm positive if any one of the codes in the algorithm appeared at least once between 1 April 2002 and 31 March 2015.
Results: The ICD-10 coding algorithm had a sensitivity of 33.7% [95% confidence interval (CI) 30.0-37.7] and a specificity of 86.2% (95% CI 75.7-92.5) for the identification of ADPKD. The provincial diagnostic billing code had a sensitivity of 91.1% (95% CI 88.5-93.1) and a specificity of 10.8% (95% CI 5.3-20.6).
Conclusions: ICD-10 coding may be useful to identify patients with a high chance of having ADPKD but fail to identify many patients with ADPKD. Provincial diagnosis billing codes identified most patients with ADPKD and also with other types of cystic kidney disease.

Keywords:  administrative data; diagnostic accuracy; polycystic kidney disease; sensitivity; specificity

DOI:  https://doi.org/10.1093/ckj/sfz184
Front Physiol. 2021 ;12 640774

Primary Cilia and Atherosclerosis.

Zhi-Mei Wang, Xiao-Fei Gao, Jun-Jie Zhang, Shao-Liang Chen.

  In artery tree, endothelial function correlates with the distribution of shear stress, a dragging force generated by flowing blood. In laminar shear stress areas, endothelial cells (ECs) are available to prevent atherosclerosis, however, ECs in disturbed shear stress sites are featured with proinflammation and atherogenesis. Basic studies in the shear stress field that focused on the mechanosensors of ECs have attracted the interest of researchers. Among all the known mechanosensors, the primary cilium is distinctive because it is enriched in disturbed shear stress regions and sparse in laminar shear stress areas. The primary cilium, a rod liked micro-organelle, can transmit extracellular mechanical and chemical stimuli into intracellular space. In the cardiovascular system, primary cilia are enriched in disturbed shear stress regions, where blood flow is slow and oscillatory, such as the atrium, downstream of the aortic valve, branches, bifurcations, and inner curves of the artery. However, in the atrioventricular canal and straight vessels, blood flow is laminar, and primary cilia can barely be detected. Primary cilia in the heart cavity prevent ECs from mesenchymal transition and calcification by suppressing transforming growth factor (TGF) signaling. Besides, primary cilia in the vascular endothelium protected ECs against disturbed shear stress-induced cellular damage by triggering Ca2+ influx as well as nitric oxide (NO) release. Moreover, primary cilia inhibit the process of atherosclerosis. In the current review, we discussed ciliogenesis, ciliary structure, as well as ciliary distribution, function and the coordinate signal transduction with shear stress in the cardiovascular system.

Keywords:  axoneme; endothelial cells; mechanical sensor; primary cilia; shear stress; vesicle trafficking

DOI:  https://doi.org/10.3389/fphys.2021.640774
Mol Biol Cell. 2021 Feb 24. mbcE20030190

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone.

Antonia Wiegering, Renate Dildrop, Christine Vesque, Hemant Khanna, Sylvie Schneider-Maunoury, Christoph Gerhardt.

A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.

DOI: https://doi.org/10.1091/mbc.E20-03-0190
Front Endocrinol (Lausanne). 2020 ;11 622581

Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1.

Taylor Landry, Daniel Shookster, Hu Huang.

  Rho-kinase 1 (ROCK1) has been implicated in diverse metabolic functions throughout the body, with promising evidence identifying ROCK1 as a therapeutic target in diabetes and obesity. Considering these metabolic roles, several pharmacological inhibitors have been developed to elucidate the mechanisms underlying ROCK1 function. Y27632 and fasudil are two common ROCK1 inhibitors; however, they have varying non-specific selectivity to inhibit other AGC kinase subfamily members and whole-body pharmacological approaches lack tissue-specific insight. As a result, interpretation of studies with these inhibitors is difficult, and alternative approaches are needed to elucidate ROCK1's tissue specific metabolic functions. Fortunately, recent technological advances utilizing molecular carriers or genetic manipulation have facilitated discovery of ROCK1's tissue-specific mechanisms of action. In this article, we review the tissue-specific roles of ROCK1 in the regulation of energy balance and substrate utilization. We highlight prominent metabolic roles in liver, adipose, and skeletal muscle, in which ROCK1 regulates energy expenditure, glucose uptake, and lipid metabolism via inhibition of AMPK2α and paradoxical modulation of insulin signaling. Compared to ROCK1's roles in peripheral tissues, we also describe contradictory functions of ROCK1 in the hypothalamus to increase energy expenditure and decrease food intake via leptin signaling. Furthermore, dysregulated ROCK1 activity in either of these tissues results in metabolic disease phenotypes. Overall, tissue-specific approaches have made great strides in deciphering the many critical metabolic functions of ROCK1 and, ultimately, may facilitate the development of novel treatments for metabolic disorders.

Keywords:  Rho-kinase; energy balance; glucose metabolism; lipid metabolism; metabolism

DOI:  https://doi.org/10.3389/fendo.2020.622581
J Hum Genet. 2021 Feb 20.

Characterization of early postzygotic somatic mutations through multi-organ analysis.

Hyeonjin Lee, Eun Na Kim, Ji-Young Lee, Ji Hun Kim, Ji-Hye Oh, Won-Kyung Kim, Eun Jeong Cho, Jinyeong Lim, Sung-Min Chun, Chang Ohk Sung.

Mosaicisms caused by postzygotic mutational events are of increasing interest because of their potential association with various human diseases. Postzygotic somatic mutations have not been well characterized however in terms of their developmental lineage in humans. We conducted whole-genome sequencing (WGS) and targeted deep sequencing in 15 organs across three developmental lineages from a single male fetus with polycystic kidney disease (PKD) of 21 weeks gestational age. This fetus had no detectable neurological abnormalities at autopsy but germline mutations in the PKHD1 gene were identified that may have been associated with the PKD. Eight early embryonic mosaic variants with no alteration of protein function were detected. These variants were thought to have occurred at the two or four cell stages after fertilization with a mutational pattern involving frequent C>T and T>C transitions. In our current analyses, no tendency toward organ-specific mutation occurrences was found as the eight variants were detected in all 15 organs. However different allele fractions of these variants were found in different organs, suggesting a tissue-specific asymmetric growth of cells that reflected the developmental germ layer of each organ. This indicated that somatic mutation occurrences, even in early embryogenesis, can affect specific organ development or disease. Our current analyses demonstrate that multi-organ analysis is helpful for understanding genomic mosaicism. Our results also provide insights into the biological role of mosaicism in embryonic development and disease.

DOI: https://doi.org/10.1038/s10038-021-00908-y
Rev Med Suisse. 2021 Feb 24. 17(727): 399-404

[Clinical use of tolvaptan: a 2021 review].

Olivier Bonny, Pierre-Yves Martin, Fabien Stucker.

Along with the arrival of the first vasopressin-receptor V2R inhibitor, the indications for its use have increased. We review here and focus on polycystic kidney disease (PKD) and hyponatremia. Tolvaptan is the first drug available to slow down the progression of PKD in patients with rapid progressing disease. However, the benefits are moderate and the side effects are important, making important to share the decision of treatment together with the patient. Hyponatremia with preserved extra-cellular volume or associated with edema may be reversed by tolvaptan. Patients with SIADH or hyponatremia and edema might benefit from this treatment under strict monitoring. Overall, vaptans are helpful in several conditions, but remain tools that must be used under close control.
Life Sci. 2021 Feb 23. pii: S0024-3205(21)00239-3. [Epub ahead of print] 119254

Piezo1 regulates intestinal epithelial function by affecting the tight junction protein claudin-1 via the ROCK pathway.

Yudong Jiang, Jun Song, Yan Xu, Caiyuan Liu, Wei Qian, Tao Bai, Xiaohua Hou.

   AIMS: Defective tight junctions (TJs) can induce intestinal epithelial dysfunction, which participates in various diseases such as irritable bowel syndrome. However, the mechanisms of TJ defects remain unclear. Our study revealed the role of Piezo1 in regulating intestinal epithelial function and TJs.
MATERIALS AND METHODS: The human colonic adenocarcinoma cell line Caco-2 were cultured on Transwell plate to form an epithelial barrier in vitro, and Piezo1 expression was manipulated using a lentivirus vector. Epithelial function was evaluated by measuring transepithelial electronic resistance (TEER) and 4-kDa FITC-dextran (FD4) transmission. TJ proteins (claudin-1, occludin, ZO-1) were evaluated by RT-PCR, western blot, and immunostaining analysis. Potential signal pathways, including the ROCK and Erk pathways, were detected. Moreover, to explore the regulatory effect of Piezo1 activity on epithelial function, inhibitors (ruthenium red, GsMTx4) and an agonist (Yoda1) were introduced both ex vivo and in vitro.
KEY FINDINGS: Alteration of Piezo1 expression altered epithelial function and the expression of the tight junction protein claudin-1. Piezo1 expression regulated phosphorylated ROCK1/2 expression, whereas interference on ROCK1/2 prevented the regulation of claudin-1 by Piezo1. In both Caco-2 monolayer and mouse colon epithelium, Piezo1 activity directly modulated epithelial function and permeability.
SIGNIFICANCE: Piezo1 negatively regulates epithelial barrier function by affecting the expression of claudin-1. Such regulation may be achieved partially via the ROCK1/2 pathway. Moreover, activating Piezo1 can induce epithelial dysfunction.

Keywords:  Claudin-1; Erk; FITC-dextran; GsMTx4; Intestinal epithelial function; Occludin; Piezo1; ROCK; Tight junction; U46619; Y-27632; Yoda1; ZO-1

DOI:  https://doi.org/10.1016/j.lfs.2021.119254
PLoS Comput Biol. 2021 Feb 26. 17(2): e1008764

Extracellular matrix density regulates the formation of tumour spheroids through cell migration.

Inês G Gonçalves, Jose Manuel Garcia-Aznar.

In this work, we show how the mechanical properties of the cellular microenvironment modulate the growth of tumour spheroids. Based on the composition of the extracellular matrix, its stiffness and architecture can significantly vary, subsequently influencing cell movement and tumour growth. However, it is still unclear exactly how both of these processes are regulated by the matrix composition. Here, we present a centre-based computational model that describes how collagen density, which modulates the steric hindrance properties of the matrix, governs individual cell migration and, consequently, leads to the formation of multicellular clusters of varying size. The model was calibrated using previously published experimental data, replicating a set of experiments in which cells were seeded in collagen matrices of different collagen densities, hence producing distinct mechanical properties. At an initial stage, we tracked individual cell trajectories and speeds. Subsequently, the formation of multicellular clusters was also analysed by quantifying their size. Overall, the results showed that our model could accurately replicate what was previously seen experimentally. Specifically, we showed that cells seeded in matrices with low collagen density tended to migrate more. Accordingly, cells strayed away from their original cluster and thus promoted the formation of small structures. In contrast, we also showed that high collagen densities hindered cell migration and produced multicellular clusters with increased volume. In conclusion, this model not only establishes a relation between matrix density and individual cell migration but also showcases how migration, or its inhibition, modulates tumour growth.

DOI: https://doi.org/10.1371/journal.pcbi.1008764
Dev Growth Differ. 2021 Feb 22.

Wnt/β-catenin signaling: structure, assembly and endocytosis of the signalosome.

Gabriele Colozza, Bon-Kyoung Koo.

  Wnt/β-catenin signaling is an ancient pathway that regulates key aspects of embryonic development, cell differentiation, proliferation and adult stem cell homeostasis. Work from different laboratories has shed light on the molecular mechanisms underlying the Wnt pathway, including structural details of ligand-receptor interactions. One key aspect that has emerged from multiple studies is that endocytosis of the receptor complex plays a crucial role in fine-tuning Wnt/β-catenin signaling. Endocytosis is a key process involved in both activation as well as attenuation of Wnt signaling, but how this is regulated is still poorly understood. Importantly, recent findings show that Wnt also regulates central metabolic pathways such as the acquisition of nutrients through actin-driven endocytic mechanisms. In this review, we propose that the Wnt pathway displays diverse characteristics that go beyond the regulation of gene expression, through a connection with the endocytic machinery.

Keywords:  Wnt/β-catenin; endocytosis; macropinocytosis; multivesicular endosomes; signalosome

DOI:  https://doi.org/10.1111/dgd.12718