scholarly journals EGFR activity is required for renal tubular cell dedifferentiation and proliferation in a murine model of folic acid-induced acute kidney injury

2013 ◽  
Vol 304 (4) ◽  
pp. F356-F366 ◽  
Author(s):  
Song He ◽  
Na Liu ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Wild Type ◽  
Cell Dedifferentiation ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Proliferation of dedifferentiated intrinsic renal tubular cells has been recognized to be the major cellular event that contributes to renal repair after acute kidney injury (AKI). However, the underlying mechanism that initiates renal tubular dedifferentiation in vivo remains unexplored. Here we investigated whether epidermal growth factor receptor (EGFR) mediates this process in a murine model of folic acid (FA)-induced AKI using waved-2 mice that have reduced tyrosine kinase activity of EGFR and gefitinib, a specific EGFR inhibitor. Administration of FA for 48 h induced EGFR phosphorylation in the kidney of wild-type mice, but this was inhibited in waved-2 mice and wild-type mice given gefitinib. Compared with wild-type mice, waved-2 mice and wild-type mice treated with gefitinib had increased renal dysfunction, histologic damage, and tubular cell apoptosis after FA administration. PAX2, a dedifferentiation marker, and proliferating cell nuclear antigen, a proliferating marker, were highly expressed in renal tubular cells in wild-type mice; however, their expression was largely inhibited in the kidney of waved-2 mice. Inhibition of EGFR with gefitinib also blocked FA-induced expression of these two proteins in wild-type mice. Moreover, FA exposure resulted in phosphorylation of AKT, a downstream signaling molecule of the phosphatidylinositol 3-kinases pathway associated with renal epithelial proliferation in wild-type mice, and its phosphorylation was totally suppressed in waved-2 mice and wild-type mice given gefitinib. Taken together, these results suggest that EGFR activation is essential for initiation of renal tubular cell dedifferentiation and proliferation after AKI.

Effects of targeted Bcl-2 expression in mitochondria or endoplasmic reticulum on renal tubular cell apoptosis

2008 ◽  
Vol 294 (3) ◽  
pp. F499-F507 ◽  
Author(s):  
Kirti Bhatt ◽  
Leping Feng ◽  
Navjotsingh Pabla ◽  
Kebin Liu ◽  
Sylvia Smith ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cytochrome C ◽  
Cell Apoptosis ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Wild Type ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Bcl-2 family proteins are central regulators of apoptosis. As the prototypic member, Bcl-2 protects various types of cells against apoptotic insults. In mammalian cells, Bcl-2 has a dual subcellular localization, in mitochondria and endoplasmic reticulum (ER). The respective roles played by mitochondrial and ER-localized Bcl-2 in apoptotic inhibition are unclear. Using Bcl-2 constructs for targeted subcellular expression, we have now determined the contributions of mitochondrial and ER-localized Bcl-2 to the antiapoptotic effects of Bcl-2 in renal tubular cells. Wild-type Bcl-2, when expressed in renal proximal tubular cells, showed partial colocalizations with both cytochrome c and disulfide isomerase, indicating dual localizations of Bcl-2 in mitochondria and ER. In contrast, Bcl-2 constructs with mitochondria-targeting or ER-targeting sequences led to relatively restricted Bcl-2 expression in mitochondria and ER, respectively. Expression of wild-type and mitochondrial Bcl-2 showed significant inhibitory effects on tubular cell apoptosis that was induced by cisplatin or ATP depletion; however, ER-Bcl-2 was much less effective. During ATP depletion, cytochrome c was released from mitochondria into the cytosol. This release was suppressed by wild-type and mitochondrial Bcl-2, but not by ER-Bcl-2. Consistently, wild-type and mitochondrial Bcl-2, but not ER-Bcl-2, blocked Bax activation during ATP depletion, a critical event for mitochondrial outer membrane permeabilization and cytochrome c release. In contrast, ER-Bcl-2 protected against apoptosis during tunicamycin-induced ER stress. Collectively, the results suggest that the cytoprotective effects of Bcl-2 in different renal injury models are largely determined by its subcellular localizations.

Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tomoaki Nagao ◽  
Takafumi Okura ◽  
Akiko Tanino ◽  
Ken-ichi Miyoshi ◽  
Masayoshi Kukida ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Injury ◽  
Immunohistochemical Analysis ◽  
Tubular Injury ◽  
Histological Changes ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear. The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI). AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice. These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.

scholarly journals RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism

2018 ◽  
Vol 115 (7) ◽  
pp. E1475-E1484 ◽  
Author(s):  
Wenjing Liu ◽  
Binbin Chen ◽  
Yang Wang ◽  
Chenling Meng ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Apical Membrane ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Wild Type ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Proximal Tubular

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK′963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.

scholarly journals HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells

2017 ◽  
Vol 313 (4) ◽  
pp. F906-F913 ◽  
Author(s):  
Wei Zhang ◽  
Xiangjun Zhou ◽  
Qisheng Yao ◽  
Yutao Liu ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Cell Injury ◽  
Hypoxia Inducible Factor ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes.

scholarly journals Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury

2020 ◽  
Vol 319 (6) ◽  
pp. F1015-F1026
Author(s):  
Wei Zhang ◽  
Yinjie Guan ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Acute Kidney Injury ◽  
Hdac Inhibitor ◽  
Cell Apoptosis ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Intercellular Adhesion Molecule ◽  
Renal Tubular Cell ◽  
Renoprotective Effect ◽  
Renal Tubular ◽  
Class Iia Hdacs

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

Enhanced sodium-dependent extrusion of magnesium in mutant cells established from a mouse renal tubular cell line

2005 ◽  
Vol 289 (4) ◽  
pp. F742-F748 ◽  
Author(s):  
Masaru Watanabe ◽  
Masato Konishi ◽  
Ichiro Ohkido ◽  
Senya Matsufuji
Keyword(s):  
Culture Media ◽  
Cell Types ◽  
Renal Tubular Cell ◽  
Wild Type ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
In The Wild ◽  
Renal Tubular ◽  
Mutant Cells ◽  
Very High

To study the regulatory mechanisms of intracellular Mg2+ concentration ([Mg2+]i) in renal tubular cells as well as in other cell types, we established a mutant strain of mouse renal cortical tubular cells that can grow in culture media with very high extracellular Mg2+ concentrations ([Mg2+]o > 100 mM: 101Mg-tolerant cells). [Mg2+]i was measured with a fluorescent indicator furaptra (mag-fura 2) in wild-type and 101Mg-tolerant cells. The average level of [Mg2+]i in the 101Mg-tolerant cells was kept lower than that in the wild-type cells either at 51 mM or 1 mM [Mg2+]o. When [Mg2+]o was lowered from 51 to 1 mM, the decrease in [Mg2+]i was significantly faster in the 101Mg-tolerant cells than in the wild-type cells. These differences between the 101Mg-tolerant cells and the wild-type cells were abolished in the absence of extracellular Na+ or in the presence of imipramine, a known inhibitor of Na+/Mg2+ exchange. We conclude that Na+-dependent Mg2+ transport activity is enhanced in the 101Mg-tolerant cells. The enhanced Mg2+ extrusion may prevent [Mg2+]i increase to higher levels and may be responsible for the Mg2+ tolerance.

scholarly journals Small Heat Shock Protein Beta-1 (HSPB1) Is Upregulated and Regulates Autophagy and Apoptosis of Renal Tubular Cells in Acute Kidney Injury

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0126229 ◽  
Author(s):  
Tatsuki Matsumoto ◽  
Madoka Urushido ◽  
Haruna Ide ◽  
Masayuki Ishihara ◽  
Kazu Hamada-Ode ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Kidney Injury ◽  
Small Heat Shock Protein ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

scholarly journals Novel Evidence of Acute Kidney Injury in COVID-19

2020 ◽  
Vol 9 (11) ◽  
pp. 3547
Author(s):  
Ti-I Chueh ◽  
Cai-Mei Zheng ◽  
Yi-Chou Hou ◽  
Kuo-Cheng Lu
Keyword(s):  
Acute Kidney Injury ◽  
Angiotensin Converting Enzyme ◽  
Kidney Injury ◽  
Host Cells ◽  
Current Evidence ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

Sign in / Sign up

Export Citation Format

Share Document