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.

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.

Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity

2005 ◽  
Vol 289 (5) ◽  
pp. F1123-F1133 ◽  
Author(s):  
Tetsuhiro Tanaka ◽  
Ichiro Kojima ◽  
Takamoto Ohse ◽  
Reiko Inagi ◽  
Toshio Miyata ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Functional Role ◽  
Hypoxia Inducible Factor ◽  
Tubular Cell ◽  
Apoptotic Cells ◽  
Outer Medulla ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Hypoxia-inducible factor (HIF)-1 is a transcription factor mediating cellular response to hypoxia. Although it is expressed in tubular cells of the ischemic kidney, its functional role is not fully clarified in the pathological context. In this study, we investigated a role of HIF in tubular cell apoptosis induced by cisplatin. HIF-1α was expressed in tubular cells in the outer medulla 3 days after cisplatin (6 mg/kg) administration. With the in vivo administration of cobalt to activate HIF, the number of apoptotic renal tubular cells became much smaller in the outer medulla, compared with the vehicle group. We also examined the functional role of HIF-1 in vitro using immortalized rat proximal tubular cells (IRPTC). In hypoxia, IRPTC that express dominant-negative (dn) HIF-1α showed impaired survival in cisplatin injury at variable doses (25–100 μM, 24 h), which was not obvious in normoxia. The observed difference in cell viability in hypoxia was associated with the increased number of apoptotic cells in dnHIF-1α clones (Hoechst 33258 staining). Studies on intracellular signaling revealed that the degree of cytochrome c release, dissipation of mitochondrial membrane potentials, and caspase-9 activity were all more prominent in dnHIF-1α clones than in control IRPTC, pointing to the accelerated signaling of mitochondrial pathways. We propose that HIF-1 mediates cytoprotection against cisplatin injury in hypoxic renal tubular cells, by reducing the number of apoptotic cells through stabilization of mitochondrial membrane integrity and suppression of apoptosis signaling. A possibility was suggested that activation of HIF-1 could be a new promising therapeutic target for hypoxic renal diseases.

scholarly journals Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching

2021 ◽  
Vol 320 (3) ◽  
pp. F454-F463
Author(s):  
Yu Zhao ◽  
Xiang-Yang Zhu ◽  
Turun Song ◽  
Lei Zhang ◽  
Alfonso Eirin ◽  
...  
Keyword(s):  
Cell Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Macrophage Function ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Factor Α ◽  
Inflammatory Macrophages ◽  
Necrosis Factor

Tumor necrosis factor-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.

scholarly journals Polarized Expression of Tamm-Horsfall Protein by Renal Tubular Epithelial Cells Activates Human Granulocytes

2002 ◽  
Vol 70 (5) ◽  
pp. 2650-2656 ◽  
Author(s):  
B. Kreft ◽  
W. J. Jabs ◽  
T. Laskay ◽  
M. Klinger ◽  
W. Solbach ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Defense ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Tubular Epithelial Cells ◽  
Bacterial Killing ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Human Granulocytes ◽  
Renal Tubular

ABSTRACT In renal bacterial infections granulocytes are of major importance in the primary immune defense against invading pathogens. However, the mechanisms of granulocytic activation in renal interstitial invasion have not been clarified. Renal tubular epithelial cell mechanisms inducing granulocytic activation and bacterial killing may include tubular cell expression of Tamm-Horsfall protein (THP), a urinary protein that is known to enhance cytokine expression in monocytes. We studied the role of THP in granulocytic activation. A strong binding of THP to human granulocytes was demonstrated by fluorescence-activated cell sorter analysis. Urinary THP and supernatants of THP-expressing cultured tubular epithelial cells (MDCK) enhanced interleukin-8 (IL-8) expression by human granulocytes. Renal tubular cells growing polarized on polycarbonate membranes were used to study apical versus basal THP expression. By electron microscopy THP immunoreactivity was exclusively found on the apical surfaces of tubular cells and was absent on the basolateral cell membrane. In the apical cell culture compartment we found significantly more stimulatory activity for granulocytic IL-8 expression. CD62L, a selectin less expressed in activated granulocytes, was decreased in granulocytes incubated with urinary THP and in supernatants of THP-producing renal tubular cells but not in supernatants from THP-negative cells. Again, the effect on CD62L expression was found only in apical culture media and was absent in the basal compartment. In summary our data give evidence that renal tubular cell THP expression may be relevant in kidney diseases since THP is a potent activator of human granulocytes. The regulation of apical versus basal THP expression and release in vivo may be crucial in the induction of the inflammatory response, e.g., in bacterial renal diseases.

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.

scholarly journals MicroRNA-140-5p ameliorates the high glucose-induced apoptosis and inflammation through suppressing TLR4/NF-κB signaling pathway in human renal tubular epithelial cells

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Jie Su ◽  
Jian Ren ◽  
Haiyan Chen ◽  
Bo Liu
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Cell Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Abstract Hyperglycemia-induced renal tubular cell injury is thought to play a critical role in the pathogenesis of diabetic nephropathy (DN). However, the role of miRNAs in renal tubular cell injury remains to be fully elucidated. The aim of the present study was to investigate the role and mechanisms of miRNAs protecting against high glucose (HG)-induced apoptosis and inflammation in renal tubular cells. First, we analyzed microRNA (miRNA) expression profiles in kidney tissues from DN patients using miRNA microarray. It was observed that miRNA-140-5p (miR-140-5p) was significantly down-regulated in kidney tissues from patients with DN. An inverse correlation between miR-140-5p expression levels with serum proteinuria was observed in DN patients, suggesting miR-140-5p may be involved in the progression of DN. HG-induced injury in HK-2 cells was used to explore the potential role of miR-140-5p in DN. We found that miR-140-5p overexpression improved HG-induced cell injury, as evidenced by the enhancement of cell viability, and inhibition of the activity of caspase-3 and reactive oxygen species (ROS) generation. It was also observed that up-regulation of miR-140-5p suppressed HG induced the expressions of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in HK-2 cells. In addition, TLR4, one of the upstream molecules of NF-κB signaling pathway, was found to be a direct target of miR-140-5p in the HK-2. Moreover, the HG-induced activation of NF-κB signaling pathway was inhibited by miR-140-5p overexpression. These results indicated that miR-140-5p protected HK-2 cells against HG-induced injury through blocking the TLR4/NF-κB pathway, and miR-140-5p may be considered as a potential prognostic biomarker and therapeutic target in the treatment of DN.

Role of intracellular calcium in hydrogen peroxide-induced renal tubular cell injury

1992 ◽  
Vol 263 (2) ◽  
pp. F214-F221 ◽  
Author(s):  
N. Ueda ◽  
S. V. Shah
Keyword(s):  
Trypan Blue ◽  
Cell Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Reactive Oxygen Metabolites ◽  
Acetoxymethyl Ester ◽  
Trypan Blue Exclusion ◽  
Renal Tubular Cells ◽  
Renal Tubular

Both reactive oxygen metabolites and calcium have been implicated in ischemic and toxic renal tubular cell injury. However, the role of calcium in oxidant injury to renal tubular cells has not been previously examined. In the present study we examined the role of intracellular free Ca2+ ([Ca2+]i) in H2O2-mediated injury to LLC-PK1 cells, a renal tubular epithelial cell line. H2O2 induced a significant rise in [Ca2+]i within 1 min after exposure of cells to 5 mM H2O2, with a sustained rise in [Ca2+]i during the course of experiments, reaching a value of 1.3 microM at 60 min (n = 10). The rise in [Ca2+]i preceded sublethal cell injury as measured by [3H]adenine release or irreversible cell injury as determined by trypan blue exclusion. Buffering [Ca2+]i with quin-2 (50 microM) and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA, 50 microM) was highly protective against the H2O2-induced cell injury. For example, at 120 min after exposure of cells to 5 mM H2O2, irreversible cell injury was reduced from 45 +/- 8 to 9 +/- 1% (n = 3) by quin-2. The acetoxymethyl ester of quin-2 (quin-2/AM) and BAPTA/AM did not interfere with the trypan blue exclusion assay or scavenge H2O2. Preventing mobilization of Ca2+ from intracellular storage sites using 8-(N,N-dimethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8, 10(-4) M) significantly reduced the rise in [Ca2+]i and thus prevented H2O2-mediated cytotoxicity to LLC-PK1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Bubble cells: renal tubular cells in the urinary sediment with characteristics of viability.

1991 ◽  
Vol 1 (7) ◽  
pp. 999-1004
Author(s):  
M Graber ◽  
B Lane ◽  
R Lamia ◽  
E Pastoriza-Munoz
Keyword(s):  
Acute Tubular Necrosis ◽  
Tubular Cell ◽  
Renal Diseases ◽  
Renal Tubular Cell ◽  
Urinary Sediment ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Tubular Necrosis ◽  
Fat Bodies ◽  
Renal Tubular

The urinary sediment was examined by light microscopy in 65 consecutive inpatients with renal insufficiency (not due to pre- or postrenal factors) referred to a nephrology consult service for evaluation. In the 60 patients in whom a single diagnosis was reached, the sediments of 34 (57%) contained an easily recognized cell, which we have called the "bubble cell". These cells were bizarre, large cells with a single nucleus, which appeared to contain one or more fluid-filled vesicles. Bubble cells were most prevalent in the sediment of patients with acute tubular necrosis but were also seen a variety of other renal diseases. In most patients with acute tubular necrosis, the sediment also contained "normal"-appearing renal tubular cells, muddy brown casts, and oval fat bodies which were indistinguishable from those seen in the nephrotic syndrome. By electron microscopy, the bubble cells appeared to be vacuolated renal tubular epithelial cells, which had characteristics of viable cells. Most bubble cells excluded the vital dye Trypan blue, whereas the normal-appearing renal tubular cells were typically strongly positive. It was concluded that bubble cells, often accompanied by oval fat bodies, are commonly present in the sediment of patients with acute tubular necrosis as well as many other types of renal disease. Most cells which would be classified as "normal" renal tubular cells in these sediments are dead. In contrast, the findings suggest that the bubble cell represents an injured but viable renal tubular cell. The frequent finding of oval fat bodies in the same sediments suggests that the oval fat body is also produced by tubular cell injury.

scholarly journals Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis

2010 ◽  
Vol 299 (1) ◽  
pp. F199-F206 ◽  
Author(s):  
Sung-Gyu Cho ◽  
Quansheng Du ◽  
Shuang Huang ◽  
Zheng Dong
Keyword(s):  
Outer Membrane ◽  
Cyclosporine A ◽  
Cell Apoptosis ◽  
Membrane Permeabilization ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Mitochondrial Fragmentation ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Recent studies revealed a striking morphological change of mitochondria during apoptosis. Mitochondria become fragmented and notably, the fragmentation contributes to mitochondrial outer membrane permeabilization and consequent release of apoptotic factors. In renal tubular cells, mitochondrial fragmentation involves the activation of Drp1, a key mitochondrial fission protein. However, it is unclear how Drp1 is regulated during tubular cell apoptosis. In this study, we examined Drp1 regulation during tubular cell apoptosis following ATP depletion. Rat kidney proximal tubular cells (RPTC) were subjected to azide treatment or severe hypoxia in glucose-free medium to induce ATP depletion. During ATP depletion, Drp1 was shown to be dephosphorylated at serine-637. Drp1 dephosphorylation could be suppressed by cyclosporine A and FK506, two calcineurin inhibitors. Importantly, cyclosporine A and FK506 could also prevent mitochondrial fragmentation, Bax accumulation, cytochrome c release, and apoptosis following ATP depletion in RPTC. The results suggest that calcineurin-mediated serine-637 dephosphorylation is involved in Drp1 activation during ATP depletion in renal tubular cells. Upon activation, Drp1 contributes to mitochondrial fragmentation and outer membrane permeabilization, resulting in the release of apoptogenic factors and apoptosis.

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