scholarly journals FoxM1 drives proximal tubule proliferation during repair from acute kidney injury

2018 ◽  
Author(s):  
Monica Chang-Panesso ◽  
Farid F. Kadyrov ◽  
Matthew Lalli ◽  
Haojia Wu ◽  
Shiyo Ikeda ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Kidney Injury ◽  
Acute Injury ◽  
Genetic Lineage ◽  
Proximal Tubule Cells ◽  
Epidermal Growth ◽  
Tubule Cells ◽  
Injury And Repair

AbstractThe proximal tubule has a remarkable capacity for repair after acute injury but the cellular lineage and molecular mechanisms underlying this repair response have been poorly characterized. Here, we developed a Kim-1-GFPCreERt2knockin mouse line (Kim-1-GCE), performed genetic lineage analysis after injury and measured the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones co-expressed Kim-1, Vimentin, Sox9 and Ki67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim-1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells account for repair rather than a fixed tubular progenitor. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor FoxM1 was induced early in injury, was required for epithelial proliferation, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair and we reveal a novel EGFR-FoxM1-dependent signaling pathway that drives proliferative repair after injury.

scholarly journals Combined Effects of PPARγAgonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Katherine Pegg ◽  
Jie Zhang ◽  
Carol Pollock ◽  
Sonia Saad
Keyword(s):  
Proximal Tubule ◽  
High Glucose ◽  
Water Retention ◽  
Growth Factor Receptor ◽  
Collagen Iv ◽  
Proximal Tubule Cells ◽  
Aqp1 Expression ◽  
Epidermal Growth ◽  
Tubule Cells ◽  
Human Proximal Tubule

We aimed to determine whether epidermal growth factor receptor (EGFR) inhibition, in addition to a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, prevents high-glucose-induced proximal tubular fibrosis, inflammation, and sodium and water retention in human proximal tubule cells exposed to normal glucose; high glucose; high glucose with the PPARγagonist pioglitazone or with the P-EGFR inhibitor, gefitinib; or high glucose with both pioglitazone and gefitinib. We have shown that high glucose increases AP-1 and NFκB binding activity, downstream phosphorylation of EGFR and Erk1/2, and fibronectin and collagen IV expression. Pioglitazone reversed these effects but upregulated NHE3 and AQP1 expression. Gefitinib inhibited high glucose induced fibronectin and collagen IV, and EGFR and Erk1/2 phosphorylation and reversed pioglitazone-induced increases in NHE3 and AQP1 expression. Our data suggests that combination of an EGFR inhibitor and a PPARγagonist mitigates high-glucose-induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells. Hence EGFR blockade may hold promise, not only in limiting tubulointerstitial pathology in diabetic nephropathy, but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by PPARγagonists.

scholarly journals Acute Kidney Injury in SARS-CoV-2 Infection: Direct Effect of Virus on Kidney Proximal Tubule Cells

2020 ◽  
Vol 21 (9) ◽  
pp. 3275 ◽  
Author(s):  
Manoocher Soleimani
Keyword(s):  
Acute Kidney Injury ◽  
Severe Acute Respiratory Syndrome ◽  
Proximal Tubule ◽  
Rna Viruses ◽  
Kidney Injury ◽  
The Novel ◽  
Proximal Tubule Cells ◽  
Severe Respiratory Infection ◽  
Tubule Cells ◽  
Novel Coronavirus

Coronaviruses (CoVs), including Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and the novel coronavirus disease-2 (SARS-CoV-2) are a group of enveloped RNA viruses that cause a severe respiratory infection which is associated with a high mortality [...]

Renal organic anion transporter 1 is maldistributed and diminishes in proximal tubule cells but increases in vasculature after ischemia and reperfusion

2008 ◽  
Vol 295 (6) ◽  
pp. F1807-F1816 ◽  
Author(s):  
Osun Kwon ◽  
Wei-Wei Wang ◽  
Shane Miller
Keyword(s):  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Kidney Injury ◽  
Organic Anion Transporter ◽  
Membrane Domain ◽  
Proximal Tubule Cells ◽  
Anion Transporter ◽  
Tubule Cells

Renal solute clearances are reduced in ischemic acute kidney injury. However, the mechanisms explaining how solute clearance is impaired have not been clarified. Recently, we reported that cadaveric renal allografts exhibit maldistribution of organic anion transporter 1 (OAT1) in proximal tubule cells after ischemia and reperfusion, resulting in impairment of PAH clearance. In the present study, we characterized renal OAT1 in detail after ischemia-reperfusion using a rat model. We analyzed renal OAT1 using confocal microscopy with a three-dimensional reconstruction of serial optical images, Western blot, and quantitative real-time RT-PCR. OAT1 was distributed to basolateral membranes of proximal tubule cells in controls. With ischemia, OAT1 decreased in basolateral membrane, especially in the lateral membrane domain, and appeared diffusely in cytoplasm. After reperfusion following 60-min ischemia, OAT1 often formed cytoplasmic aggregates. The staining for OAT1 started reappearing in lateral membrane domain 1 h after reperfusion. The basolateral membrane staining was relatively well discernable at 240 h of reperfusion. Of note, a distinct increase in OAT1 expression was noted in vasculature early after ischemia and after reperfusion. The total amount of OAT1 protein expression in the kidney diminished after ischemia-reperfusion in a duration-dependent manner until 72 h, when they began to recover. However, even at 240 h, the amount of OAT1 did not reach control levels. The kidney tissues tended to show a remarkable but transient increase in mRNA expression for OAT1 at 5 min of ischemia. Our findings may provide insights of renal OAT1 in its cellular localization and response during ischemic acute kidney injury and recovery from it.

scholarly journals 6-Shogaol protects against ischemic acute kidney injury by modulating NF-κB and heme oxygenase-1 pathways

2019 ◽  
Vol 317 (3) ◽  
pp. F743-F756 ◽  
Author(s):  
Sang Jun Han ◽  
Mihwa Kim ◽  
Vivette D. D’Agati ◽  
H. Thomas Lee
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Heme Oxygenase ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Mrna Synthesis ◽  
Proximal Tubule Cells ◽  
Tnf Α ◽  
Tubule Cells

Acute kidney injury (AKI) due to renal ischemia-reperfusion (I/R) is a major clinical problem without effective therapy. Ginger is one of the most widely consumed spices in the world, and 6-shogaol, a major ginger metabolite, has anti-inflammatory effects in neuronal and epithelial cells. Here, we demonstrate our novel findings that 6-shogaol treatment protected against renal I/R injury with decreased plasma creatinine, blood urea nitrogen, and kidney neutrophil gelatinase-associated lipocalin mRNA synthesis compared with vehicle-treated mice subjected to renal I/R. Additionally, 6-shogaol treatment reduced kidney inflammation (decreased proinflammatory cytokine and chemokine synthesis as well as neutrophil infiltration) and apoptosis (decreased TUNEL-positive renal tubular cells) compared with vehicle-treated mice subjected to renal I/R. In cultured human and mouse kidney proximal tubule cells, 6-shogaol significantly attenuated TNF-α-induced inflammatory cytokine and chemokine mRNA synthesis. Mechanistically, 6-shogaol significantly attenuated TNF-α-induced NF-κB activation in human renal proximal tubule cells by reducing IKKαβ/IκBα phosphorylation. Furthermore, 6-shogaol induced a cytoprotective chaperone heme oxygenase (HO)-1 via p38 MAPK activation in vitro and in vivo. Consistent with these findings, pretreatment with the HO-1 inhibitor zinc protoporphyrin IX completely prevented 6-shogaol-mediated protection against ischemic AKI in mice. Taken together, our study showed that 6-shogaol protects against ischemic AKI by attenuating NF-κB activation and inducing HO-1 expression. 6-Shogaol may provide a potential therapy for ischemic AKI during the perioperative period.

scholarly journals Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection

2020 ◽  
Author(s):  
Wei Lin ◽  
Longfei Hu ◽  
Yan Zhang ◽  
Joshua D. Ooi ◽  
Ting Meng ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Kidney Injury ◽  
Cell Types ◽  
Gene Expressions ◽  
Proximal Tubule Cells ◽  
Bladder Cell ◽  
Short Period ◽  
Tubule Cells

AbstractSince December 2019, a novel coronavirus named 2019 coronavirus (2019-nCoV) has emerged in Wuhan of China and spread to several countries worldwide within just one month. Apart from fever and respiratory complications, acute kidney injury has been observed in some patients with 2019-nCoV. In a short period of time, angiotensin converting enzyme II (ACE2), have been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same for severe acute respiratory syndrome coronavirus (SARS). To investigate the possible cause of kidney damage in 2019-nCoV patients, we used both published kidney and bladder cell atlas data and an independent unpublished kidney single cell RNA-Seq data generated in-house to evaluate ACE2 gene expressions in all cell types in healthy kidneys and bladders.Our results showed the enriched expression of all subtypes of proximal tubule cells of kidney and low but detectable levels of expression in bladder epithelial cells. These results indicated the urinary system is a potential route for 2019-nCoV infection, along with the respiratory system and digestion system. Our findings suggested the kidney abnormalities of SARS and 2019-nCoV patients may be due to proximal tubule cells damage and subsequent systematic inflammatory response induced kidney injury. Beyond that, laboratory tests of viruses and related indicators in urine may be needed in some special patients of 2019-nCoV.

scholarly journals MO331LINEAGE TRACING OF REGENERATING PROXIMAL TUBULE CELLS (STC) BY SINGLE CELL PROFILING IN ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eleni Stamellou ◽  
Mingbo Cheng ◽  
Viktor Sterzer ◽  
Katja Leuchtle ◽  
Thiago Strieder ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Single Cell ◽  
Transgenic Mouse ◽  
Ischemia Reperfusion ◽  
Expression Patterns ◽  
Kidney Injury ◽  
Multiple Time ◽  
Proximal Tubule Cells ◽  
Tubule Cells

Abstract Background and Aims Acute tubular injury accounts for the most common intrinsic cause for acute kidney injury (AKI). The scattered tubular cell (STC) phenotype was discovered as a uniform reaction of tubule cells triggered by injury. Our group was the first to identify an inducible transgenic mouse (PEC-rtTA-mouse) specifically labeling STCs with eGFP. Analysis of the transcriptional factors and associated signaling pathways might reveal the function and role of STCs in AKI. Method Here, we performed single-cell RNA sequencing of unilateral ischemia-reperfusion murine model of AKI 8, 24, 48 hours and 6 and 12 days after AKI induction. Results Genes expressing proximal tubular proteins and transporters were markedly downregulated during transition into the STC phenotype upon injury; but expression recovered over time and upon resolution and tubular cells re-differentiated into proximal tubule cells. This provides evidence for the first time that the STC phenotype is a transient and reversible phenotype triggered by injury. Among cells in the STC phenotype, we could identify 2 sub-clusters; a highly proliferating sub-cluster that in the cell cycle analysis showed the highest proportion of cycling cells. The second eGFP-positive cluster appeared very early after AKI and expressed a distinct set of genes (defined by 7 anchor genes). Some of the highly up-regulated genes are known markers of STCs hence confirming the specificity of our transgenic mouse line. Conclusion Our study provides gene expression patterns specifically in STCs upon injury and repair at multiple time points and suggests that the STC phenotype is a transient and reversible phenotype triggered by injury.

Molecular Mechanisms by Which Iron Induces Nitric Oxide Synthesis in Cultured Proximal Tubule Cells

2001 ◽  
Vol 9 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Liguang Chen ◽  
Yiping Wang ◽  
Lukas K. Kairaitis ◽  
Yang Wang ◽  
Bao-Hong Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Proximal Tubule ◽  
Molecular Mechanisms ◽  
Nitric Oxide Synthesis ◽  
Proximal Tubule Cells ◽  
Tubule Cells
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