scholarly journals Gentamicin-Induced Acute Kidney Injury in an Animal Model Involves Programmed Necrosis of the Collecting Duct

2020 ◽  
Vol 31 (9) ◽  
pp. 2097-2115 ◽  
Author(s):  
Huihui Huang ◽  
William W. Jin ◽  
Ming Huang ◽  
Heyu Ji ◽  
Diane E. Capen ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Aminoglycoside Antibiotic ◽  
Kinase Domain ◽  
Programmed Necrosis ◽  
Proximal Tubule Cells ◽  
Cell Death Pathways ◽  
Collecting Ducts ◽  
Tubule Cells

BackgroundGentamicin is a potent aminoglycoside antibiotic that targets gram-negative bacteria, but nephrotoxicity limits its clinical application. The cause of gentamicin-induced AKI has been attributed mainly to apoptosis of the proximal tubule cells. However, blocking apoptosis only partially attenuates gentamicin-induced AKI in animals.MethodsMice treated with gentamicin for 7 days developed AKI, and programmed cell death pathways were examined using pharmacologic inhibitors and in RIPK3-deficient mice. Effects in porcine and murine kidney cell lines were also examined.ResultsGentamicin caused a low level of apoptosis in the proximal tubules and significant ultrastructural alterations consistent with necroptosis, occurring predominantly in the collecting ducts (CDs), including cell and organelle swelling and rupture of the cell membrane. Upregulation of the key necroptotic signaling molecules, mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), was detected in gentamicin-treated mice and in cultured renal tubule cells. In addition, gentamicin induced apical accumulation of total and phosphorylated MLKL (pMLKL) in CDs in mouse kidney. Inhibiting a necroptotic protein, RIPK1, with necrostatin-1 (Nec-1), attenuated gentamicin-induced necrosis and upregulation of MLKL and RIPK3 in mice and cultured cells. Nec-1 also alleviated kidney inflammation and fibrosis, and significantly improved gentamicin-induced renal dysfunction in mice. Furthermore, deletion of RIPK3 in the Ripk3−/− mice significantly attenuated gentamicin-induced AKI.ConclusionsA previously unrecognized role of programmed necrosis in collecting ducts in gentamicin-induced kidney injury presents a potential new therapeutic strategy to alleviate gentamicin-induced AKI through inhibiting necroptosis.

scholarly journals Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

2019 ◽  
Vol 30 (3) ◽  
pp. 443-459 ◽  
Author(s):  
Yasunobu Ishikawa ◽  
Sorin Fedeles ◽  
Arnaud Marlier ◽  
Chao Zhang ◽  
Anna-Rachel Gallagher ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Genetic Model ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Endoplasmic Reticulum Membrane ◽  
Double Knockout ◽  
Embryonic Mouse ◽  
Interstitial Inflammation ◽  
Collecting Ducts

BackgroundSEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1–mediated polycystic kidney disease (PKD). It also activates the Ire1α-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model.MethodsWe explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1α, specifically in the collecting ducts of neonatal mice.ResultsThe later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1α-Xbp1 pathway or cause polycystin-1–dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1α in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1α.ConclusionsIn the absence of Sec63, basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.

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 Moxonidine inhibits Na+/H+ exchange in proximal tubule cells and cortical collecting duct

1997 ◽  
Vol 52 (2) ◽  
pp. 454-459 ◽  
Author(s):  
Eberhard Schlatter ◽  
Ieva Ankorina-Stark ◽  
Sabine Haxelmans ◽  
Helge Hohage
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Cortical Collecting Duct ◽  
Proximal Tubule Cells ◽  
Tubule Cells

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 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.

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