scholarly journals SOX9 is required for kidney fibrosis and regulates NAV3 to control renal myofibroblast function in mice and humans

2019 ◽  
Author(s):  
Sayyid Raza ◽  
Elliot Jokl ◽  
James Pritchett ◽  
Katherine Martin ◽  
Kim Su ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Kidney Diseases ◽  
Pharmacological Intervention ◽  
Chronic Kidney Diseases ◽  
Kidney Fibrosis ◽  
Genome Wide ◽  
Common Endpoint ◽  
Vitro Model ◽  
Novel Target

AbstractRenal fibrosis is a common endpoint for many chronic kidney diseases. Extracellular matrix (ECM) from myofibroblasts causes progressive scarring and organ failure. The mechanisms underlying fibrogenesis and how it is sustained are incompletely understood. Here, we show that the transcription factor, Sex determining region Y-box 9 (SOX9), is required for kidney fibrosis. From genome-wide analysis we identify Neuron navigator 3 (NAV3) downstream of SOX9. NAV3 was upregulated in kidney disease in patients and following renal injury in mice colocalised with SOX9. By establishing an in vitro model of renal pericyte transition to myofibroblast we demonstrated that NAV3 is required for multiple aspects of fibrogenesis including actin polymerization linked to cell migration and sustaining SOX9 and active YAP1 levels. In summary, our work discovers novel SOX9-NAV3-YAP1/SOX9 circuitry as a new mechanism to explain the progression of kidney fibrosis and points to NAV3 as a novel target for pharmacological intervention.

SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function

2021 ◽  
Vol 14 (672) ◽  
pp. eabb4282 ◽  
Author(s):  
Sayyid Raza ◽  
Elliot Jokl ◽  
James Pritchett ◽  
Katherine Martin ◽  
Kim Su ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Actin Polymerization ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Pharmacological Intervention ◽  
Kidney Fibrosis ◽  
Genome Wide ◽  
Vitro Model ◽  
Sustained Activation

Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitro model of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required for multiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation of the mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention.

scholarly journals Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

2019 ◽  
Vol 11 (486) ◽  
pp. eaat4865 ◽  
Author(s):  
Qinxue Sun ◽  
Maike Baues ◽  
Barbara M. Klinkhammer ◽  
Josef Ehling ◽  
Sonja Djudjaj ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Matrix Protein ◽  
Kidney Diseases ◽  
Therapeutic Interventions ◽  
Extracellular Matrix Protein ◽  
Imaging Method ◽  
Chronic Kidney Diseases ◽  
Kidney Fibrosis ◽  
Common Endpoint ◽  
Routine Assessment

Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

Antibodies to kidney endothelial cells contribute to a “leaky” glomerular barrier in patients with chronic kidney diseases

2012 ◽  
Vol 302 (7) ◽  
pp. F884-F894 ◽  
Author(s):  
Nidia Maritza Hernandez ◽  
Anna Casselbrant ◽  
Meghnad Joshi ◽  
Bengt R. Johansson ◽  
Suchitra Sumitran-Holgersson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Kidney Diseases ◽  
Clinical Importance ◽  
Human Kidney ◽  
Cell Permeability ◽  
Chronic Kidney Diseases ◽  
Esrd Patients

Anti-endothelial cell antibodies (AECA) have been reported to cause endothelial dysfunction, but their clinical importance for tissue-specific endothelial cells is not clear. We hypothesized that AECA reactive with human kidney endothelial cells (HKEC) may cause renal endothelial dysfunction in patients with chronic kidney diseases. We report that a higher fraction (56%) of end-stage renal disease (ESRD) patients than healthy controls (5%) have AECA reactive against kidney endothelial cells ( P <0.001). The presence of antibodies was associated with female gender ( P < 0.001), systolic hypertension ( P < 0.01), and elevated TNF-α ( P < 0.05). These antibodies markedly decrease expression of both adherens and tight junction proteins VE-cadherin, claudin-1, and zonula occludens-1 and provoked a rapid increase in cytosolic free Ca2+and rearrangement of actin filaments in HKEC compared with controls. This was followed by an enhancement in protein flux and phosphorylation of VE-cadherin, events associated with augmented endothelial cell permeability. Additionally, kidney biopsies from ESRD patients with AECA but not controls demonstrated a marked decrease in adherens and tight junctions in glomerular endothelium, confirming our in vitro data. In summary, our data demonstrate a causal link between AECA and their capacity to induce alterations in glomerular vascular permeability.

scholarly journals Downregulation of miR-503 in Activated Kidney Fibroblasts Disinhibits KCNN4 in an in Vitro Model of Kidney Fibrosis

2019 ◽  
Vol 44 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Christoph Mann ◽  
Brajesh Pratap Kaistha ◽  
Michael Kacik ◽  
Thorsten Stiewe ◽  
Joachim Hoyer
Keyword(s):  
Kidney Fibrosis ◽  
Calcium Dependent ◽  
Channel Current ◽  
Channel Expression ◽  
Pharmacological Blockade ◽  
Vitro Model ◽  
End Stage ◽  
Activated Fibroblasts

Background/Aims: Activated fibroblasts are key controllers of extracellular matrix turnover in kidney fibrosis, the pathophysiological end stage of chronic kidney disease. The proliferation of activated fibroblasts depends on the expression of the calcium-dependent potassium channel KCNN4. Expression of this ion channel is upregulated in fibrotic kidneys. Genetic and pharmacological blockade of KCNN4 inhibits fibrosis in vitro and in vivo. Methods: We studied the regulation of KCNN4 and possible involvement of miRNAs in an in-vitro fibrosis model using murine kidney fibroblasts. We tested fibroblast proliferation, channel function, channel expression and expression regulation after FGF-2 stimulation. Results: Proliferation was significantly increased by FGF-2, channel current and expression were almost doubled (+ 91% and +125%, respectively). MiRNA microarray identified upregulation of miRNA-503, which targets RAF1 and thereby controls KCNN4-expression via disinhibition of the Ras/Raf/MEK/ ERK-cascade. Conclusion: This data show a) a profound upregulation of KCNN4 in stimulated fibroblast and b) identifies miR-503 as a regulator of KCNN4 expression.

scholarly journals A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection

2004 ◽  
Vol 4 (1) ◽  
Author(s):  
Lisa FP Ng ◽  
Martin L Hibberd ◽  
Eng-Eong Ooi ◽  
Kin-Fai Tang ◽  
Soek-Ying Neo ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Model System ◽  
Host Responses ◽  
Sars Coronavirus ◽  
Genome Wide ◽  
Coronavirus Infection ◽  
In Vitro Model System ◽  
Vitro Model

scholarly journals Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold

2019 ◽  
Vol 67 (9) ◽  
pp. 643-661 ◽  
Author(s):  
Roman David Bülow ◽  
Peter Boor
Keyword(s):  
Extracellular Matrix ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Dynamic Structure ◽  
Renal Diseases ◽  
Chronic Kidney Diseases ◽  
Kidney Fibrosis ◽  
Non Invasive ◽  
Ecm Proteins ◽  
Diagnostic Approaches

Kidney fibrosis is the common histological end-point of progressive, chronic kidney diseases (CKDs) regardless of the underlying etiology. The hallmark of renal fibrosis, similar to all other organs, is pathological deposition of extracellular matrix (ECM). Renal ECM is a complex network of collagens, elastin, and several glycoproteins and proteoglycans forming basal membranes and interstitial space. Several ECM functions beyond providing a scaffold and organ stability are being increasingly recognized, for example, in inflammation. ECM composition is determined by the function of each of the histological compartments of the kidney, that is, glomeruli, tubulo-interstitium, and vessels. Renal ECM is a dynamic structure undergoing remodeling, particularly during fibrosis. From a clinical perspective, ECM proteins are directly involved in several rare renal diseases and indirectly in CKD progression during renal fibrosis. ECM proteins could serve as specific non-invasive biomarkers of fibrosis and scaffolds in regenerative medicine. The gold standard and currently only specific means to measure renal fibrosis is renal biopsy, but new diagnostic approaches are appearing. Here, we discuss the localization, function, and remodeling of major renal ECM components in healthy and diseased, fibrotic kidneys and the potential use of ECM in diagnostics of renal fibrosis and in tissue engineering.

Schlafen 11 is a novel target for mucosal regeneration in Ulcerative Colitis

2021 ◽  
Author(s):  
Sho Watanabe ◽  
Ryu Nishimura ◽  
Tomoaki Shirasaki ◽  
Nobuhiro Katsukura ◽  
Shuji Hibiya ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Microarray Analysis ◽  
In Vitro Model ◽  
Mucosal Injury ◽  
Mucosal Regeneration ◽  
Vitro Model ◽  
Novel Target

Abstract Background and Aims Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable course. Although the goal of UC therapy is to achieve mucosal healing, the pathogenesis of mucosal injury caused by chronic inflammation remains unknown. We therefore aim to elucidate molecular mechanisms of mucosal injury by establishing in vitro and in vivo humanized UC mimicking models. Methods An in vitro model using human colon organoids was established by 60 weeks of inflammatory stimulation. The key gene for mucosal injury caused by long-term inflammation was identified by microarray analysis. An in vivo model was established by xenotransplantation of organoids into mouse colonic mucosa. Results An in vitro model demonstrated that long-term inflammation induced irrecoverable changes in organoids: inflammatory response and apoptosis with oxidative stress and suppression of cell viability. This model also mimicked organoids derived from patients with UC at the gene expression and phenotype levels. Microarray analysis revealed Schlafen11 (SLFN11) was irreversibly induced by long-term inflammation. Consistently, SLFN11 was highly expressed in UC mucosa but absent in normal mucosa. The knockdown of SLFN11 (SLFN11-KD) suppressed apoptosis of IECs induced by inflammation. Moreover, SLFN11-KD improved the take rates of xenotransplantation and induced regenerative changes of crypts observed in patients with UC in remission. Conclusions In vitro and in vivo UC mimicking models were uniquely established using human colonic organoids. They revealed SLFN11 is significant for mucosal injury in UC, and its potential as a novel target for mucosal regeneration.

An In-vitro Model to Study Device-induced Thrombosis and Embolism:

2000 ◽  
Vol 83 (02) ◽  
pp. 322-326 ◽  
Author(s):  
Sivaprasad Sukavaneshvar ◽  
Syed Mohammad ◽  
Kenneth Solen
Keyword(s):  
Light Scattering ◽  
Real Time ◽  
In Vitro Model ◽  
Pharmacological Intervention ◽  
Tetraacetic Acid ◽  
Non Invasive ◽  
Prototype Device ◽  
Vitro Model ◽  
Time Assessment

SummaryA bovine in-vitro model was developed to investigate device-induced thromboembolism (TE) and its pharmacological intervention, using a stent as a prototype device. Emboli were assessed continuously using a light-scattering microemboli detector (LSMD). Thrombus on the stent was assessed gravimetrically at the end of the experiment. The contribution of the stent as the predominant source of detectable thromboemboli in this model was verified by placing LSMD probes upstream and downstream of the stent. The effectiveness of ethylenedinitrilo-tetraacetic-acid (EDTA) and three anti-thrombogenic agents (aspirin, dipyridamole, and tirofiban) for mitigating device-induced TE was also assessed. The results show that 1) the model has potential to study device-induced TE and the efficacy of possible interventional strategies, 2) the LSMD is capable of continuous, non-invasive, real-time assessment of embolism, 3) the assessment of embolization may constitute an important part of evaluating hemocompatibility, 4) tirofiban is effective in reducing both stent-induced thrombosis and embolism above certain concentrations.

scholarly journals Feline Morbillivirus, a New Paramyxovirus Possibly Associated with Feline Kidney Disease

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 501 ◽  
Author(s):  
Eun Jin Choi ◽  
Victoria Ortega ◽  
Hector C. Aguilar
Keyword(s):  
Hong Kong ◽  
Viral Entry ◽  
Tubulointerstitial Nephritis ◽  
Kidney Diseases ◽  
Chronic Kidney Diseases ◽  
Persistent Infections ◽  
Stray Cats ◽  
Potential Association ◽  
Entry Mechanism

Feline morbillivirus (FeMV) was first isolated in stray cats in Hong Kong in 2012. Since its discovery, the virus has been reported in domestic cats worldwide, including in Hong Kong, Japan, Italy, US, Brazil, Turkey, UK, Germany, and Malaysia. FeMV is classified in the Morbillivirus genus within the Paramyxoviridae family. FeMV research has focused primarily on determining the host range, symptoms, and characteristics of persistent infections in vitro. Importantly, there is a potential association between FeMV infection and feline kidney diseases, such as tubulointerstitial nephritis (TIN) and chronic kidney diseases (CKD), which are known to significantly affect feline health and survival. However, the tropism and viral entry mechanism(s) of FeMV remain unknown. In this review, we summarize the FeMV studies up to date, including the discoveries of various FeMV strains, basic virology, pathogenicity, and disease signs.

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