bims-bicyki 2020-12-13 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2020‒12‒13
twenty-one papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants.
Suspected Pulmonary Embolism Postcesarean Section in a Patient with Autosomal Dominant Polycystic Kidney Disease.
Primary ciliary dyskinesia: a major player in a bigger game.
Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease.
Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease.
Primary ciliary dyskinesia relative protein ZMYND10 is involved in regulating ciliary function and intraflagellar transport in Paramecium tetraurelia.
Complications in Patients With Autosomal Dominant Polycystic Kidney Disease Undergoing Ureteroscopy: A Cohort Study.
Primary Ciliary Signaling in the Skin-Contribution to Wound Healing and Scarring.
Occurrence of Portal Hypertension and Its Clinical Course in Patients With Molecularly Confirmed Autosomal Recessive Polycystic Kidney Disease (ARPKD).
Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway.
Renal hemodynamic and protective effects of renoactive drugs in type 2 diabetes: interaction with SGLT2 inhibitors.
An RGDKGE containing cryptic collagen fragment regulates phosphorylation of LATS1 and controls ovarian tumor growth by a YAP-dependent mechanism.
FOP Negatively Regulates Ciliogenesis and Promotes Cell Cycle Re-entry by Facilitating Primary Cilia Disassembly.
Biomarkers of inflammation and repair in kidney disease progression.
A role for Cep70 in centriole amplification in multiciliated cells.
p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway.
Transient rho-associated coiled-coil containing kinase (ROCK) inhibition on human retinal pigment epithelium results in persistent Rho/ROCK downregulation.
NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output.
The Collagen-Based Medical Device MD-Tissue Acts as a Mechanical Scaffold Influencing Morpho-Functional Properties of Cultured Human Tenocytes.
Activation of yes-associated protein mediates sphingosine-1-phosphate-induced proliferation and migration of pulmonary artery smooth muscle cells and its potential mechanisms.
Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer.

Contemp Clin Trials Commun. 2020 Sep;19 100635

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants.

Kristen L Nowak, Heather Farmer-Bailey, Melissa A Cadnapaphornchai, Zhiying You, Diana George, Wei Wang, Anna Jovanovich, Danielle E Soranno, Berenice Gitomer, Michel Chonchol.

  Although often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6-25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.

Keywords:  ADPKD; Clinical trial; Flow-mediated dilation; Pediatric; Pulse-wave velocity; Total kidney volume

DOI:  https://doi.org/10.1016/j.conctc.2020.100635
Niger Med J. 2020 Jul-Aug;61(4):61(4): 223-225

Suspected Pulmonary Embolism Postcesarean Section in a Patient with Autosomal Dominant Polycystic Kidney Disease.

Olusegun O Badejoko, Olufunke F Dada, Akaninyene E Ubom, Olumuyiwa T Ajayeoba.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetically inherited kidney disease worldwide. It is however relatively underdiagnosed in Africans because its diagnosis is often incidental. During pregnancy, ADPKD is associated with increased risk of preeclampsia and venous thromboembolism. The case of a 33-year-old lady incidentally diagnosed with ADPKD during pregnancy is presented. She developed preeclampsia at term and had cesarean delivery of twins. She however suffered cardiopulmonary arrest postoperatively and this created a treatment dilemma because therapeutic anticoagulation which was the primary treatment for her suspected pulmonary embolism was absolutely contraindicated if the actual cause of her collapse was ruptured cerebral aneurysm which was also a feature of ADPKD. We decided to resuscitate aggressively and perform an urgent cranial computed tomography which ruled out intracranial hemorrhage. We then commenced anticoagulation and she made an excellent recovery. This case illustrates the importance of a timely multidisciplinary approach to patient management.

Keywords:  Anticoagulation; cardiopulmonary arrest; cerebral aneurysm; polycystic kidney disease; postpartum collapse; pulmonary embolism

DOI:  https://doi.org/10.4103/nmj.NMJ_99_20
Breathe (Sheff). 2020 Jun;16(2): 200047

Primary ciliary dyskinesia: a major player in a bigger game.

Reena Bhatt, Claire Hogg.

Primary ciliary dyskinesia (PCD) is an inherited disorder of clinical and genetic heterogeneity resulting from mutations in genes involved in the transport, assembly and function of motile cilia. The resulting impairment in mucociliary clearance means patients suffer from chronic progressive lung disease, bronchiectasis, rhinosinusitis and middle ear disease. Subfertility is common to both male and female patients. Situs abnormalities occur in around half of patients, with a subgroup suffering more complex situs arrangements where congenital heart defects or other organ abnormalities frequently coexist. Variations from the classical PCD phenotype are increasingly recognised where overlapping features across a range of motile and nonmotile ciliopathies are redefining our approach to both diagnosis and management of these complex conditions. PCD offers an ideal opportunity for direct visualisation of ciliary function and structure, following nasal brush biopsy, allowing opportunities for researchers to directly interrogate the downstream impact of loss of function mutations. In turn, this has led to rapid advances in the development of new diagnostic tests. These advances mean that PCD is an excellent disease model for understanding the genetic and mechanistic causes of the clinical phenotype for all respiratory ciliopathies. Furthermore, the overlapping role of motile ciliary defects in a wider set of complex and syndromic disorders related to loss of function mutations in primary, nonmotile cilia has been recognised. As we better understand the role of ciliary defects in a broad spectrum of diseases, we should aim to map out a framework through which we can identify, diagnose and treat all respiratory ciliopathies.Key points: Primary ciliary dyskinesia is just one of a group of conditions where a heterogeneous array of genetic mutations affect the assembly or structure of motile cilia.Overlapping phenotypes between motile and nonmotile ciliopathies are redefining the diagnostic and therapeutic approach to encompass all ciliopathy patients with a respiratory phenotype.An extended diagnostic algorithm may be required to capture the majority of cases with a respiratory ciliopathy, including patients with syndromic ciliopathies.The terminology around disorders of motile cilia is becoming more descriptive to better reflect the heterogeneity and underlying disease mechanisms across the spectrum of respiratory ciliopathies.
Educational aims: To summarise the existing knowledge base around the disease mechanisms for respiratory ciliopathies, including primary ciliary dyskinesia (PCD).To explore and understand the reasons for changing terminology around respiratory ciliopathies.To emphasise key messages around the diagnosis and treatment of all ciliopathies.Diagnosing PCD is complex and time consuming, and there is no single stand-alone test that can confirm or exclude a diagnosis in all cases.

DOI: https://doi.org/10.1183/20734735.0047-2020
Kidney Int Rep. 2020 Dec;5(12): 2341-2350

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease.

Claudia Izzi, Chiara Dordoni, Laura Econimo, Elisa Delbarba, Francesca Romana Grati, Eva Martin, Cinzia Mazza, Gianfranco Savoldi, Luca Rampoldi, Federico Alberici, Francesco Scolari.

  Introduction: In humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease.Methods: We describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations.
Results: Significant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense.
Conclusion: HNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants.

Keywords:  ADPKD; ADTKD; CAKUT; HNF1B; RCAD; cystic kidney disease; medullary sponge kidney; nephrogenic diabetes; tubulointerstitial nephritis

DOI:  https://doi.org/10.1016/j.ekir.2020.09.042
Kidney360. 2020 Jul;1(7): 648-656

Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease.

Laura Grau, Berenice Gitomer, Bryan McNair, Myles Wolf, Peter Harris, Godela Brosnahan, Vicente Torres, Theodore Steinman, Alan Yu, Arlene Chapman, Michel Chonchol, Kristen L Nowak.

Background: Higher serum intact fibroblast growth factor 23 (iFGF23) was associated with disease progression in participants with autosomal dominant polycystic kidney disease (ADPKD) in the HALT-PKD Studies. PKD mutation is also an important determinant of progression. We hypothesized that serum levels of iFGF23 and vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25[OH]D]) differ according to ADPKD mutation and differentially predict clinical end points according to genotype (significant interaction between genotype and mineral metabolites).Methods: A total of 864 individuals with ADPKD who participated in the HALT-PKD Study A or B and had measurements of mineral metabolites (1,25[OH]2D, 25[OH]D, iFGF23) were categorized by PKD mutation (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]). The association of the interactions of genotype × iFGF23, genotype × 1,25(OH)2D, and genotype × 25(OH)D with (1) annualized change in eGFR; (2) mean annualized percentage change in height-corrected total kidney volume (Study A only); and (3) time to a composite of 50% reduction in eGFR, ESKD, or death were evaluated using linear regression and Cox proportional hazards regression.
Results: Median (interquartile range) iFGF23 differed (PKD1 truncating, 55.8 [40.7-76.8]; PKD1 nontruncating, 49.9 [37.7-71.0]; PKD2, 49.0 [33.8-70.5]; NMD, 50.3 [39.7-67.4] pg/ml; P=0.03) and mean±SD 1,25(OH)2D differed (PKD1 truncating, 32.8±12.8; PKD1 nontruncating, 33.4±12.5; PKD2, 34.1±13.1; NMD, 38.0±14.6 pg/ml; P=0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype (P=0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH)2D or 25(OH)D and genotype for clinical end points.
Conclusions: ADPKD genotype interacts significantly with FGF23 to influence clinical end points. Whereas the worst outcomes were in individuals with a PKD1-truncating or -nontruncating mutation and the highest iFGF23 tertile, risk of the composite end point differed according to iFGF23 the most in the PKD1-nontruncating and PKD2 groups.

DOI: https://doi.org/10.34067/KID.0001692020
Eur J Protistol. 2020 Nov 22. pii: S0932-4739(20)30086-9. [Epub ahead of print]77 125756

Primary ciliary dyskinesia relative protein ZMYND10 is involved in regulating ciliary function and intraflagellar transport in Paramecium tetraurelia.

Lei Shi, Xiangyu Shen, Yuhao Chi, Yuan Shen.

  Cilia are highly conserved in most eukaryotes and are regarded as an important organelle for motility and sensation in various species. Cilia are microscopic, hair-like cytoskeletal structures that protrude from the cell surface. The major focus in studies of cilia has been concentrated on the ciliary dysfunction in vertebrates that causes multisymptomatic diseases, which together are referred to as ciliopathies. To date, the understanding of ciliopathies has largely depended on the study of ciliary structure and function in different animal models. Zinc finger MYND-type containing 10 (ZMYND10) is a ciliary protein that was recently found to be mutated in patients with primary ciliary dyskinesia (PCD). In Paramecium tetraurelia, we identified two ZMYND10 genes, arising from a whole-genome duplication. Using RNAi, we found that the depletion of ZMYND10 in P. tetraurelia causes severe ciliary defects, thus provoking swimming dysfunction and lethality. Moreover, we found that the absence of ZMYND10 caused the abnormal localization of the intraflagellar transport (IFT) protein IFT43 along cilia. These results suggest that ZMYND10 is involved in the regulation of ciliary function and IFT, which may contribute to the study of PCD pathogenesis.

Keywords:  Cilia; Ciliogenesis; IFT; Paramecium; ZMYND10

DOI:  https://doi.org/10.1016/j.ejop.2020.125756
Can J Kidney Health Dis. 2020 ;7 2054358120972830

Complications in Patients With Autosomal Dominant Polycystic Kidney Disease Undergoing Ureteroscopy: A Cohort Study.

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

  Background: Ureteroscopy is a minimally invasive treatment option for upper tract stones. The distorted kidney anatomy in patients with autosomal dominant polycystic kidney disease (ADPKD) may place them at higher risk for ureteroscopic complications.Objective: To compare the 30-day risk of ureteroscopic complications between patients with and without ADPKD.
Design: Retrospective cohort study.
Setting: Ontario, Canada.
Patients: Seventy three patients with ADPKD and 81 445 patients without ADPKD who underwent ureteroscopy for upper urinary tract stones between April 1, 2002, and March 1, 2018.
Measurements: A 30-day risk of (1) hospital presentation with ureteroscopic complications (which was a composite outcome of either emergency department visit or hospital admission with acute kidney injury, urinary tract infection, or sepsis); (2) all-cause hospital presentation; (3) all-cause hospital admission; and (4) all-cause emergency department visit.
Methods: We regressed outcomes on demographic variables, health care use in the prior 1-year, various procedures and comorbidities related to the outcome in the prior 5 years, and prescribed medications filled in the past 120 days using modified Poisson regression to compare the risk ratio (RR) of each outcome between patients with and without ADPKD.
Results: The median (interquartile, IQR) age was 44 (38-60 years) in the ADPKD group and 53 (42-64) in the control group. About 40% were women in both groups. The risk of ureteroscopic complications was not significantly different in patients with versus without ADPKD (8.2% vs 4.3%; adjusted RR = 1.5, 95% confidence interval [CI] = 0.7-3.2). Patients with versus without ADPKD were more likely to present to hospital after their procedure (35.6% vs. 20.0%; adjusted RR = 1.6, 95% CI = 1.2-2.2), which included a statistically significant increase in the risk of presenting to the emergency department (32.9% vs. 19.0%; adjusted RR = 1.6, 95% CI = 1.1-2.2) but not hospital admissions (10.9% vs. 5.0%; adjusted RR = 1.8, 95% CI = 0.9-3.4).
Limitations: The low numbers of events led to imprecision around the estimates.
Conclusion: Patients with ADPKD have a higher risk of return to the hospital within 30 days of ureteroscopy for stone disease.
Trial registration: We did not register this study.

Keywords:  administrative data; autosomal dominant polycystic kidney disease; epidemiology; stones

DOI:  https://doi.org/10.1177/2054358120972830
Front Cell Dev Biol. 2020 ;8 578384

Primary Ciliary Signaling in the Skin-Contribution to Wound Healing and Scarring.

Mayu Hosio, Viljar Jaks, Heli Lagus, Jyrki Vuola, Rei Ogawa, Esko Kankuri.

  Primary cilia (PC) are solitary, post-mitotic, microtubule-based, and membrane-covered protrusions that are found on almost every mammalian cell. PC are specialized cellular sensory organelles that transmit environmental information to the cell. Signaling through PC is involved in the regulation of a variety of cellular processes, including proliferation, differentiation, and migration. Conversely, defective, or abnormal PC signaling can contribute to the development of various pathological conditions. Our knowledge of the role of PC in organ development and function is largely based on ciliopathies, a family of genetic disorders with mutations affecting the structure and function of PC. In this review, we focus on the role of PC in their major signaling pathways active in skin cells, and their contribution to wound healing and scarring. To provide comprehensive insights into the current understanding of PC functions, we have collected data available in the literature, including evidence across cell types, tissues, and animal species. We conclude that PC are underappreciated subcellular organelles that significantly contribute to both physiological and pathological processes of the skin development and wound healing. Thus, PC assembly and disassembly and PC signaling may serve as attractive targets for antifibrotic and antiscarring therapies.

Keywords:  cell signaling; fibroblast; inflammation; myofibroblast; primary cilia; scar formation; wound healing

DOI:  https://doi.org/10.3389/fcell.2020.578384
Front Pediatr. 2020 ;8 591379

Occurrence of Portal Hypertension and Its Clinical Course in Patients With Molecularly Confirmed Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Dorota Wicher, Ryszard Grenda, Mikołaj Teisseyre, Marek Szymczak, Paulina Halat-Wolska, Dorota Jurkiewicz, Max Christoph Liebau, Elżbieta Ciara, Małgorzata Rydzanicz, Joanna Kosińska, Krystyna Chrzanowska, Irena Jankowska.

  Purpose: Liver involvement in autosomal recessive polycystic kidney disease (ARPKD) leads to the development of portal hypertension and its complications. The aim of this study was to analyze the occurrence of the portal hypertension and its clinical course and the dynamics in patients with molecularly confirmed ARPKD in a large Polish center. Moreover, the available options in diagnostics, prevention and management of portal hypertension in ARPKD will be discussed. Materials and Methods: The study group consisted of 17 patients aged 2.5-42 years. All patients had ARPKD diagnosis confirmed by molecular tests. Retrospective analysis included laboratory tests, ultrasound and endoscopic examinations, transient elastography and clinical evaluation. Results: Any symptom of portal hypertension was established in 71% of patients. Hypersplenism, splenomegaly, decreased portal flow and esophageal varices were found in 47, 59, 56, and 92% of patients, respectively. Gastrointestinal bleeding occurred in four of 17 patients. Endoscopic variceal ligation (EVL) was performed at least once in nine patients with esophageal varices. Conclusions: Portal hypertension and its complications are present in a significant percentage of ARPKD patients. They should be under the care of multidisciplinary nephrology-gastroenterology/hepatology team. Complications of portal hypertension may occur early in life. Endoscopic methods of preventing gastroesophageal bleeding, such as endoscopic variceal ligation, are effective and surgical techniques, including liver transplantation, are required rarely.

Keywords:  autosomal recessive polycystic kidney disease; endoscopic variceal ligation; liver fibrosis; molecular confirmation; portal hypertension; transient elastography

DOI:  https://doi.org/10.3389/fped.2020.591379
J Cell Biol. 2021 Jan 04. pii: e202002026. [Epub ahead of print]220(1):

Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway.

Sarah Findakly, Vikas Daggubati, Galo Garcia, Sydney A LaStella, Abrar Choudhury, Cecilia Tran, Amy Li, Pakteema Tong, Jason Q Garcia, Natasha Puri, Jeremy F Reiter, Libin Xu, David R Raleigh.

Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.

DOI: https://doi.org/10.1083/jcb.202002026
Nephrology (Carlton). 2020 Dec 06.

Renal hemodynamic and protective effects of renoactive drugs in type 2 diabetes: interaction with SGLT2 inhibitors.

Rosalie A Scholtes, Michaël J B van Baar, Megan D Kok, Petter Bjornstad, David Z I Cherney, Jaap A Joles, Daniël H van Raalte.

  Diabetic kidney disease remains the leading cause of end stage kidney disease and a major risk factor for cardiovascular disease. Large cardiovascular outcome trials and dedicated kidney trials have shown that sodium-glucose cotransporter (SGLT)2 inhibitors reduce cardiovascular morbidity and mortality and attenuate hard renal outcomes in patients with type 2 diabetes (T2D). Underlying mechanisms explaining these renal benefits may be mediated by decreased glomerular hypertension, possibly by vasodilation of the postglomerular arteriole. Patients with T2D often receive several different drugs, some of which could also impact the renal vasculature, and could therefore modify both renal efficacy and safety of SGLT2 inhibition. The most commonly prescribed drugs that could interact with SGLT2 inhibitors on renal hemodynamic function include renin-angiotensin system inhibitors, calcium channel blockers, and diuretics. Herein we review the effects of these drugs on renal hemodynamic function in patients with T2D and focus on studies that measured glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) with gold-standard techniques. In addition, we posit, based on these observations, potential interactions with SGLT2 inhibitors with an emphasis on efficacy and safety. This article is protected by copyright. All rights reserved.

Keywords:  RAS inhibitors; SGLT2 inhibition; calcium channel blockers; diabetic kidney disease; diuretics; renal hemodynamic function; type 2 diabetes humans

DOI:  https://doi.org/10.1111/nep.13839
Am J Pathol. 2020 Dec 08. pii: S0002-9440(20)30550-2. [Epub ahead of print]

An RGDKGE containing cryptic collagen fragment regulates phosphorylation of LATS1 and controls ovarian tumor growth by a YAP-dependent mechanism.

XiangHua Han, Jennifer M Caron, Christine W Lary, Pradeep Sathyanarayana, Calvin Vary, Peter C Brooks.

  The growth and spread of malignant tumors such as ovarian carcinomas are governed in part by complex interconnected-signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. Here, we provide evidence that blocking cellular interactions with an RGDKGE-containing collagen peptide that selectively binds integrin β3 on ovarian tumor cells, enhances the phosphorylation of the hippo effector kinase LATS1, and reduces nuclear accumulation of YAP and its target gene c-Myc. Selectively targeting this RGDKGE-containing collagen fragment inhibited ovarian tumor growth and the development of ascites fluid in vivo. These findings suggest that this bioactive collagen fragment may represent a previously unknown regulator of the hippo effector kinase LATS1 and regulates ovarian tumor growth by a YAP dependent mechanism. Taken together, these data not only provide new mechanistic insight into how a unique collagen fragment may regulate ovarian cancer, but in addition may help provide a potentially useful new alternative strategy to control ovarian tumor progression based on selectively disrupting a previously unappreciated signaling cascade.

Keywords:  Collagen; Extracellular Matrix; Integrin αvβ3; LATS1; Ovarian Carcinoma; Stroma; YAP

DOI:  https://doi.org/10.1016/j.ajpath.2020.11.009
Front Cell Dev Biol. 2020 ;8 590449

FOP Negatively Regulates Ciliogenesis and Promotes Cell Cycle Re-entry by Facilitating Primary Cilia Disassembly.

Huadong Jiang, Shanshan Liu, Man-Hei Cheung, Aftab Amin, Chun Liang.

  Primary cilia are microtubule-based, antenna-like organelles, which are formed in G0 phase and resorbed as cells re-enter the cell cycle. It has been reported that primary cilia can influence the timing of cell cycle progression. However, the molecular links between ciliogenesis and cell cycle progression are not well understood. The Fibroblast Growth Factor Receptor 1 Oncogene Partner (FOP) has been implicated in ciliogenesis, but its function in ciliogenesis is not clear. Here, we show that FOP plays a negative role in ciliogenesis. Knockdown of FOP promotes cilia elongation and suppresses cilia disassembly. In contrast, ectopic expression of FOP induces defects in primary cilia formation, which can be rescued by either pharmacological or genetic inhibition of Aurora kinase A which promotes cilia disassembly. Moreover, knockdown of FOP delays cell cycle re-entry of quiescent cells following serum re-stimulation, and this can be reversed by silencing Intraflagellar Transport 20 (IFT20), an intraflagellar transport member essential for ciliogenesis. Collectively, these results suggest that FOP negatively regulates ciliogenesis and can promote cell cycle re-entry by facilitating cilia disassembly.

Keywords:  AURKA; FOP; cell cycle exit and re-entry; cilia assembly and disassembly; primary cilia

DOI:  https://doi.org/10.3389/fcell.2020.590449
J Clin Invest. 2020 Dec 08. pii: 139927. [Epub ahead of print]

Biomarkers of inflammation and repair in kidney disease progression.

Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G Coca, Amit X Garg, Jonathan Himmelfarb, Pavan K Bhatraju, Talat Alp Ikizler, Edward Siew, Lorraine B Ware, Kathleen D Liu, Alan S Go, James S Kaufman, Paul L Kimmel, Vernon M Chinchilli, Lloyd Cantley, Chirag R Parikh.

  INTRODUCTION: Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision-making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODS: We enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein-1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.
RESULTS: Higher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.
CONCLUSIONS: Biomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.
FUNDING: National Institutes of Health grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01HL085757, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, R01DK093771, K01DK120783, P30DK079310, P30DK114809.

Keywords:  Chronic kidney disease; Clinical practice; Inflammation; Molecular diagnosis; Nephrology

DOI:  https://doi.org/10.1172/JCI139927
Dev Biol. 2020 Dec 04. pii: S0012-1606(20)30309-2. [Epub ahead of print]

A role for Cep70 in centriole amplification in multiciliated cells.

Sun K Kim, Eva Brotslaw, Virginie Thome, Jen Mitchell, Rosa Ventrella, Caitlin Collins, Brian Mitchell.

  Centriole amplification in multiciliated cells occurs in a pseudo-cell cycle regulated process that typically utilizes a poorly characterized molecularly dense structure called the deuterosome. We identified the centrosomal protein Cep70 as a novel deuterosome-associated protein that forms a complex with other deuterosome proteins, CCDC78 and Deup1. Cep70 dynamically associates with deuterosomes during centriole amplification in the ciliated epithelia of Xenopus embryos. Cep70 is not found in nascent deuterosomes prior to amplification. However, it becomes localized at deuterosomes at the onset of centriole biogenesis and remains there after the completion of centriole amplification. Deuterosome localization requires a conserved C-terminal "Cep70" motif. Depletion of Cep70 using morpholino oligos or CRISPR/Cas9 editing in F0 embryos leads to a severe decrease in centriole formation in both endogenous MCCs, as well as ectopically induced MCCs. Consistent with a decrease in centrioles, endogenous MCCs have defects in the process of radial intercalation. We propose that Cep70 represents a novel regulator of centriole biogenesis in MCCs.

Keywords:  Centriole amplification; Cep70; Deuterosome; Multiciliated cell; Radial intercalation

DOI:  https://doi.org/10.1016/j.ydbio.2020.11.011
Front Cardiovasc Med. 2020 ;7 542485

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway.

Rei J Abe, Hannah Savage, Masaki Imanishi, Priyanka Banerjee, Sivareddy Kotla, Jesus Paez-Mayorga, Jack Taunton, Keigi Fujiwara, Jong Hak Won, Syed Wamique Yusuf, Nicolas L Palaskas, Jose Banchs, Steven H Lin, Keri L Schadler, Jun-Ichi Abe, Nhat-Tu Le.

  Previously, we reported that post-translational modifications (PTMs) of MAGI1, including S741 phosphorylation and K931 de-SUMOylation, both of which are regulated by p90RSK activation, lead to endothelial cell (EC) activation. However, roles for p90RSK and MAGI1-PTMs in regulating EC permeability remain unclear despite MAGI1 being a junctional molecule. Here, we show that thrombin (Thb)-induced EC permeability, detected by the electric cell-substrate impedance sensing (ECIS) based system, was decreased by overexpression of dominant negative p90RSK or a MAGI1-S741A phosphorylation mutant, but was accelerated by overexpression of p90RSK, siRNA-mediated knockdown of magi1, or the MAGI1-K931R SUMOylation mutant. MAGI1 depletion also increased the mRNA and protein expression of the large tumor suppressor kinases 1 and 2 (LATS1/2), which inhibited YAP/TAZ activity and increased EC permeability. Because the endothelial barrier is a critical mediator of tumor hypoxia, we also evaluated the role of p90RSK activation in tumor vessel leakiness by using a relatively low dose of the p90RSK specific inhibitor, FMK-MEA. FMK-MEA significantly inhibited tumor vessel leakiness at a dose that does not affect morphology and growth of tumor vessels in vivo. These results provide novel insights into crucial roles for p90RSK-mediated MAGI1 PTMs and the Hippo pathway in EC permeability, as well as p90RSK activation in tumor vessel leakiness.

Keywords:  EC permeability; Hippo pathway; MAGI1; SUMOylation; p90RSK

DOI:  https://doi.org/10.3389/fcvm.2020.542485
Biochem Biophys Rep. 2020 Dec;24 100841

Transient rho-associated coiled-coil containing kinase (ROCK) inhibition on human retinal pigment epithelium results in persistent Rho/ROCK downregulation.

Shohei Kitahata, Hinako Ichikawa, Yuji Tanaka, Tatsuya Inoue, Kazuaki Kadonosono.

  Retinal pigment epithelium (RPE) cells is the outermost layer of the retina and RPE dysfunction is a key factor in the disease pathogenesis of age-related macular degeneration (AMD). Transplantation therapy using induced pluripotent stem cell (iPSC)-derived RPEs has recently received much attention as a treatment for AMD. Preserving these cells under the best possible conditions is important, and preservation methods using Y-27632 have been reported. Rho-associated coiled-coil containing kinase (ROCK) inhibitors are known to inhibit cell death, emerging as important drug candidates for stem cell differentiation and regenerative medicine. However, it has recently been shown that ROCK inhibitors may have a vasodilatory effect on human retinal arterioles, a side effect that should ideally be avoided in RPE transplantation. Although ROCK inhibitors hold great potential, optimizing efficacy while minimizing adverse reactions is critical for translation into a clinical treatment. We examined the effect of transient exposure of RPE cells to ROCK inhibitor Y-27632 to determine whether the extracellular presence of the drug is necessary for ongoing Rho/ROCK downregulation. Human RPE cells were subcultured as a suspension for 4 h in drug-free medium following exposure to Y-27632 for 2 h. A Y-27632 concentration of >10 μM improved cell survival beyond 4 h and cell proliferation in recovery culture medium. ROCK2 expression levels were specifically downregulated by Y-27632 in the Rho/ROCK signaling pathway. In conclusion, we demonstrated that the effect of Y-27632 is not dependent on its extracellular availability and can last beyond the 2 h of exposure. The lasting Rho/ROCK signaling pathway downregulation by Y-27632 suggests that RPE cell transplantation with ROCK inhibitor-free media is possible, which can minimize side effects to host tissue and have wider implications for transplantation methods requiring ROCK inhibition.

Keywords:  Cell preservation; Retinal pigment epithelium; Rho-associated coiled-coil containing kinase (ROCK) inhibitor; Transient exposure

DOI:  https://doi.org/10.1016/j.bbrep.2020.100841
Cancers (Basel). 2020 Dec 07. pii: E3666. [Epub ahead of print]12(12):

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output.

Md Imtiaz Khalil, Ishita Ghosh, Vibha Singh, Jing Chen, Haining Zhu, Arrigo De Benedetti.

  Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.

Keywords:  MS-determined phosphopeptides; NIMA-related kinase 1 (NEK1); thioridazine (THD); tousled-like kinase (TLK); yes-associated protein 1 (YAP1)

DOI:  https://doi.org/10.3390/cancers12123666
Cells. 2020 Dec 08. pii: E2641. [Epub ahead of print]9(12):

The Collagen-Based Medical Device MD-Tissue Acts as a Mechanical Scaffold Influencing Morpho-Functional Properties of Cultured Human Tenocytes.

Filippo Randelli, Patrizia Sartori, Cristiano Carlomagno, Marzia Bedoni, Alessandra Menon, Elena Vezzoli, Michele Sommariva, Nicoletta Gagliano.

  Mechanotransduction is the ability of cells to translate mechanical stimuli into biochemical signals that can ultimately influence gene expression, cell morphology and cell fate. Tenocytes are responsible for tendon mechanical adaptation converting mechanical stimuli imposed during mechanical loading, thus affecting extracellular matrix homeostasis. Since we previously demonstrated that MD-Tissue, an injectable collagen-based medical compound containing swine-derived collagen as the main component, is able to affect tenocyte properties, the aim of this study was to analyze whether the effects triggered by MD-Tissue were based on mechanotransduction-related mechanisms. For this purpose, MD-Tissue was used to coat Petri dishes and cytochalasin B was used to deprive tenocytes of mechanical stimulation mediated by the actin cytoskeleton. Cell morphology, migration, collagen turnover pathways and the expression of key mechanosensors were analyzed by morphological and molecular methods. Our findings confirm that MD-Tissue affects collagen turnover pathways and favors cell migration and show that the MD-Tissue-induced effect represents a mechanical input involving the mechanotransduction machinery. Overall, MD-Tissue, acting as a mechanical scaffold, could represent an effective medical device for a novel therapeutic, regenerative and rehabilitative approach to favor tendon healing in tendinopathies.

Keywords:  YAP/TAZ; actin cytoskeleton; collagen turnover; mechanotransduction; medical device; tendinopathy; tendon; tenocytes

DOI:  https://doi.org/10.3390/cells9122641
J Cell Physiol. 2020 Dec 07.

Activation of yes-associated protein mediates sphingosine-1-phosphate-induced proliferation and migration of pulmonary artery smooth muscle cells and its potential mechanisms.

Wenhua Shi, Qingting Wang, Jian Wang, Xin Yan, Wei Feng, Qianqian Zhang, Cui Zhai, Limin Chai, Shaojun Li, Xinming Xie, Manxiang Li.

  The aims of the present study were to examine the molecular mechanisms underlying sphingosine-1-phosphate (S1P)-induced rat pulmonary artery smooth muscle cells (PASMCs) proliferation/migration and to determine the effect of yes-associated protein (YAP) activation on S1P-induced PASMCs proliferation/migration and its potential mechanisms. S1P induced YAP dephosphorylation and nuclear translocation, upregulated microRNA-130a/b (miR-130a/b) expression, reduced bone morphogenetic protein receptor 2 (BMPR2), and inhibitor of DNA binding 1(Id1) expression, and promoted PASMCs proliferation and migration. Pretreatment of cells with Rho-associated protein kinase (ROCK) inhibitor Y27632 suppressed S1P-induced YAP activation, miR-130a/b upregulation, BMPR2/Id1 downregulation, and PASMCs proliferation/migration. Knockdown of YAP using small interfering RNA also suppressed S1P-induced alterations of miR-130a/b, BMPR2, Id1, and PASMCs behavior. In addition, luciferase reporter assay indicated that miR-130a/b directly regulated BMPR2 expression in PASMCs. Inhibition of miR-130a/b functions by anti-miRNA oligonucleotides attenuated S1P-induced BMPR2/Id1 downregulation and the proliferation and migration of PASMCs. Taken together, our study indicates that S1P induces activation of YAP through ROCK signaling and subsequently increases miR-130a/b expression, which, in turn, downregulates BMPR2 and Id1 leading to PASMCs proliferation and migration.

Keywords:  S1P; YAP; pulmonary artery hypertension; pulmonary artery smooth muscle cells

DOI:  https://doi.org/10.1002/jcp.30193
Nat Biomed Eng. 2020 Dec 07.

Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer.

Minjeong Jang, Jinhyeon An, Seung Won Oh, Joo Yeon Lim, Joon Kim, Jung Kyoon Choi, Jae-Ho Cheong, Pilnam Kim.

In many cancers, tumour progression is associated with increased tissue stiffness. Yet, the mechanisms associating tissue stiffness with tumorigenesis and malignant transformation are unclear. Here we show that in gastric cancer cells, the stiffness of the extracellular matrix reversibly regulates the DNA methylation of the promoter region of the mechanosensitive Yes-associated protein (YAP). Reciprocal interactions between YAP and the DNA methylation inhibitors GRHL2, TET2 and KMT2A can cause hypomethylation of the YAP promoter and stiffness-induced oncogenic activation of YAP. Direct alteration of extracellular cues via in situ matrix softening reversed YAP activity and the epigenetic program. Our findings suggest that epigenetic reprogramming of the mechanophysical properties of the extracellular microenvironment of solid tumours may represent a therapeutic strategy for the inhibition of cancer progression.

DOI: https://doi.org/10.1038/s41551-020-00657-x