Chromatin accessibility of kidney tubular cells under stress reveals key transcription factor mediating acute and chronic kidney disease

FEBS Journal ◽  
2021 ◽  
Author(s):  
Yuexian Xing ◽  
Qi Wang ◽  
Jing Zhang ◽  
Wenju Li ◽  
Aiping Duan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Chromatin Accessibility ◽  
Tubular Cells ◽  
Kidney Tubular Cells

scholarly journals Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3292
Author(s):  
Kuo Zhou ◽  
Xuexue Zhu ◽  
Ke Ma ◽  
Jibin Liu ◽  
Bernd Nürnberg ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Protein Abundance ◽  
Rt Pcr ◽  
Calcium Sensing Receptor ◽  
Transcript Levels ◽  
Calcium Sensing ◽  
Store Depletion

In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.

scholarly journals Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease

2013 ◽  
Vol 83 (6) ◽  
pp. 1029-1041 ◽  
Author(s):  
Stacey Ruiz ◽  
Pablo E. Pergola ◽  
Richard A. Zager ◽  
Nosratola D. Vaziri
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Kidney Disease

scholarly journals MO038SCARF EXPRESSION IN KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Sol Carriazo ◽  
Maria Dolores Sanchez-Nino ◽  
Maria Vanessa Perez Gomez ◽  
Laura Castañeda-Infante ◽  
Catalina Martin ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Risk Factor ◽  
Kidney Disease ◽  
Single Cell ◽  
Kidney Tissue ◽  
Differentially Expressed ◽  
Tubular Cells ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Impact

Abstract Background and Aims Chronic kidney disease (CKD) is the most common risk factor for lethal COVID19 and the risk factor that most increases the risk of death of COVID19 patients. Additionally, acute kidney injury (AKI) is frequent in COVID19 and AKI increases the risk of death. However, the underlying cellular and molecular mechanisms of such increased risk are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) are required for and/or regulate (in a positive or negative manner) coronary cell entry and/or viral replication. We have now studied changes in the expression of genes encoding for SCARF in the context of acute and chronic kidney disease. Method Data mining of in-house (experimental models of AKI -folic acid nephropathy- and CKD -Unilateral ureteral obstruction- in mice) and publicly available databases (Nephroseq, published single cell transcriptomics studies) of kidney tissue transcriptomics as well as the Protein Atlas database. Results Out of 28 SCARF genes identified by Singh et al (Cell Reports 2020), 26 were represented in the experimental AKI database. Of them 7 (27%) were differentially expressed during AKI (FDR <0.05), 4 of them upregulated and 3 downregulated (Figure 1.A). Additionally, 27 were represented in the experimental CKD database. Of them 17 (63%) were differentially expressed during experimental CKD, 6 of them upregulated and 11 downregulated (Figure 1.B). Two genes were consistently upregulated (Ctsl and Ifitm3) and two consistently downregulated (Tmprss2 and Top3b) in both experimental AKI and CKD (Figure 1.A and B). They encode cathepsin L, interferon induced transmembrane protein 3, transmembrane serine protease 2, DNA topoisomerase III beta, respectively. Single cell transcriptomics databases localized Ctsl expression mainly to podocytes and tubular cells while protein atlas showed clear tubular staining. The main site of Ifitm3 was endothelium in both datasets and it was also localized to leukocytes by single cell transcriptomics. Tmprss2 was mainly localized to tubular cells in both datasets while Top3b was widely expressed in parenchymal renal cells, endothelium and leucocytes in single cell transcriptomics. Increased kidney expression of Ifitm3 and decreased expression of Tmprss2 and Top3b were confirmed in diverse CKD datasets in Nephroseq. Conclusion Both AKI and CKD are associated with differential expression of SCARF genes in kidney tissue, the impact of CKD appearing to be larger. Characterization of these changes and their functional impact in kidney tissue and beyond the kidneys may provide clues to the increased risk of severe or lethal COVID19 in kidney disease patients. Kidney SCARF gene expression

scholarly journals Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

2020 ◽  
Vol 21 (21) ◽  
pp. 8131
Author(s):  
Deepika Watts ◽  
Diana Gaete ◽  
Diego Rodriguez ◽  
David Hoogewijs ◽  
Martina Rauner ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Iron Metabolism ◽  
Blood Cells ◽  
Hypoxia Inducible Factor ◽  
Altered Expression ◽  
Master Regulators ◽  
Complex Process

Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

scholarly journals Role of SIK1 in the transition of acute kidney injury into chronic kidney disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinxiu Hu ◽  
Jiao Qiao ◽  
Qun Yu ◽  
Bing Liu ◽  
Junhui Zhen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Kidney Injury ◽  
High Morbidity ◽  
Mesenchymal Transition ◽  
Immunohistochemistry Staining ◽  
Hk2 Cells

Abstract Background Acute kidney injury (AKI), with a high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have showed that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD transition. However, whether SIK1 is involved in AKI-CKD transition and by what mechanism it regulates AKI-CKD transition remains unknown. Methods We firstly detected the expression of SIK1 in kidney tissues of AKI patients and AKI mice by immunohistochemistry staining, and then we established Aristolochic acid (AA)-induced AKI-CKD transition model in C57BL/6 mice and HK2 cells. Subsequently, we performed immunohistochemistry staining, ELISA, real-time PCR, Western blot, immunofluorescence staining and Transwell assay to explore the role and underlying mechanism of SIK1 on AKI-CKD transition. Results The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1 mediated AA-induced AKI-CKD transition by regulating WNT/β-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of WNT/β-catenin pathway and its downstream transcription factor Twist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD transition. Conclusions Our study demonstrated, for the first time, a protective role of SIK1 in AKI-CKD transition by regulating WNT/β-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment AKI-CKD transition in the future.

scholarly journals Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486

2012 ◽  
Vol 82 (4) ◽  
pp. 401-411 ◽  
Author(s):  
Jing Xu ◽  
Rongshan Li ◽  
Biruh Workeneh ◽  
Yanlan Dong ◽  
Xiaonan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Muscle Wasting

scholarly journals Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

2020 ◽  
Vol 21 (7) ◽  
pp. 2483 ◽  
Author(s):  
Camélia Makhloufi ◽  
Fanny Nicolas ◽  
Nathalie McKay ◽  
Samantha Fernandez ◽  
Guillaume Hache ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Renal Insufficiency ◽  
Knockout Mice ◽  
Cardiovascular Complications ◽  
Crystal Deposition ◽  
Metabolism Enzymes ◽  
Low Levels

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR−/− males. AhR−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

scholarly journals The Aryl Hydrocarbon Receptor in Chronic Kidney Disease: Friend or Foe?

2020 ◽  
Vol 8 ◽  
Author(s):  
Yenan Mo ◽  
Zhaoyu Lu ◽  
Lixin Wang ◽  
Chunlan Ji ◽  
Chuan Zou ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Kidney Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Cell Cycle Progression ◽  
Current Knowledge ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Cellular Processes ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes cell responses to small molecules derived from the diet, microorganisms, metabolism and pollutants. The AhR signal regulates many basic cellular processes, including cell cycle progression, adhesion, migration, apoptosis and cell proliferation. Many studies have shown that AhR is associated with chronic kidney disease (CKD) and its complications. This article reviews the current knowledge about the role of AhR in CKD, showing that AhR mediates CKD complications, including cardiovascular disease, anemia, bone disorders, cognitive dysfunction and malnutrition, and that it influences drug metabolism in individuals with CKD. AhR enhances the intestinal barrier function to reduce the harmful effects of uremic toxins. Therefore, understanding the complex roles of AhR during CKD is important to be able to target this transcription factor safely and effectively for CKD prevention and treatment.

Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease

2013 ◽  
Vol 304 (5) ◽  
pp. F471-F480 ◽  
Author(s):  
Eun-Sun Ryu ◽  
Mi Jin Kim ◽  
Hyun-Soo Shin ◽  
Yang-Hee Jang ◽  
Hack Sun Choi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Uric Acid ◽  
Kidney Disease ◽  
Organic Anion ◽  
Mesenchymal Transition ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Phenotypic Transition ◽  
E Cadherin

Recent experimental and clinical studies suggest a causal role of uric acid in the development of chronic kidney disease. Most studies have focused on uric acid-induced endothelial dysfunction, oxidative stress, and inflammation in the kidney. The direct effects of uric acid on tubular cells have not been studied in detail, and whether uric acid can mediate phenotypic transition of renal tubular cells such as epithelial-to-mesenchymal transition (EMT) is not known. We therefore investigated whether uric acid could alter E-cadherin expression and EMT in the kidney of hyperuricemic rats and in cultured renal tubular cells (NRK cells). Experimental hyperuricemia was associated with evidence of EMT before the development of significant tubulointerstitial fibrosis at 4 wk, as shown by decreased E-cadherin expression and an increased α-smooth muscle actin (α-SMA). Allopurinol significantly inhibited uric acid-induced changes in E-cadherin and α-SMA with an amelioration of renal fibrosis at 6 wk. In cultured NRK cells, uric acid induced EMT, which was blocked by the organic anion transport inhibitor probenecid. Uric acid increased expression of transcriptional factors associated with decreased synthesis of E-cadherin (Snail and Slug). Uric acid also increased the degradation of E-cadherin via ubiquitination, which is of importance since downregulation of E-cadherin is considered to be a triggering mechanism for EMT. In conclusion, uric acid induces EMT of renal tubular cells decreasing E-cadherin synthesis via an activation of Snail and Slug as well as increasing the degradation of E-cadherin.

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