Inhibition of apoptosis by Zn2+ in renal tubular cells following ATP depletion

2004 ◽  
Vol 287 (3) ◽  
pp. F492-F500 ◽  
Author(s):  
Qingqing Wei ◽  
Jinzhao Wang ◽  
Mong-Heng Wang ◽  
Fushin Yu ◽  
Zheng Dong
Keyword(s):  
Cytochrome C ◽  
Renal Cell ◽  
Atp Depletion ◽  
Caspase Activation ◽  
Renal Protection ◽  
Cytochrome C Release ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Apoptosis has been implicated in ischemic renal injury. Thus one strategy of renal protection is to antagonize apoptosis. However, apoptosis inhibitory approaches remain to be fully explored. Zn2+ has long been implicated in apoptosis inhibition; but systematic analysis of the inhibitory effects of Zn2+ is lacking. Moreover, whether Zn2+ blocks renal cell apoptosis following ischemia is unknown. Here, we demonstrate that Zn2+ is a potent apoptosis inhibitor in an in vitro model of renal cell ischemia. ATP depletion induced apoptosis in cultured renal tubular cells, which was accompanied by caspase activation. Zn2+ at 10 μM inhibited both apoptosis and caspase activation, whereas Co2+ was without effect. In ATP-depleted cells, Zn2+ partially prevented Bax activation and cytochrome c release from mitochondria. In isolated cell cytosol, Zn2+ blocked cytochrome c-stimulated caspase activation at low-micromolar concentrations. In addition, Zn2+ could directly antagonize the enzymatic activity of purified recombinant caspases. We conclude that Zn2+ is a potent inhibitor of apoptosis in renal tubular cells following ATP depletion. Zn2+ blocks apoptosis at multiple steps including Bax activation, cytochrome c release, apoptosome function, and caspase activation.

Acidic pH inhibits ATP depletion-induced tubular cell apoptosis by blocking caspase-9 activation in apoptosome

2005 ◽  
Vol 289 (2) ◽  
pp. F410-F419 ◽  
Author(s):  
Craig Brooks ◽  
Pimonrat Ketsawatsomkron ◽  
Yang Sui ◽  
Jinzhao Wang ◽  
Cong-Yi Wang ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cell Apoptosis ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Acidic Ph ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Tubular Cells

Tubular cell apoptosis has been implicated in the development of ischemic renal failure. In in vitro models, ATP depletion-induced apoptosis of tubular cells is mediated by the intrinsic pathway involving Bax translocation, cytochrome c release, and caspase activation. While the apoptotic cascade has been delineated, much less is known about its regulation. The current study has examined the regulation of ATP depletion-induced tubular cell apoptosis by acidic pH, a common feature of tissue ischemia. Cultured renal tubular cells were subjected to 3 h of ATP depletion with azide and then recovered in full culture medium. The treatment led to apoptosis in ∼40% of cells. Apoptosis was significantly reduced, if the pH of ATP depletion buffer was lowered from 7–7.4 to 6–6.5. This was accompanied by the inhibition of caspase activation. However, acidic pH did not prevent Bax translocation and oligomerization in mitochondria. Cytochrome c release from mitochondria was not blocked either, suggesting that acidic pH inhibited apoptosis at the postmitochondrial level. To determine the postmitochondrial events that were blocked by acidic pH, we conducted in vitro reconstitution experiments. Exogenous cytochrome c, when added into isolated cell cytosol, induced caspase activation. Such activation was abrogated, when pH during the reconstitution was lowered to 6 or 6.5. Nevertheless, acidic pH did not prevent the recruitment and association of caspase-9 by Apaf-1, as shown by coimmunoprecipitation. Together, this study demonstrated the inhibition of tubular cell apoptosis following ATP depletion by acidic pH. A critical step blocked by acidic pH seems to be caspase-9 activation in apoptosome.

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.

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.

The Effects of Cyclosporine on Protein Expression of P53 and Transforming Growth Factor-Beta in Human Renal Tubular Cells

2000 ◽  
Vol 6 (S2) ◽  
pp. 604-605
Author(s):  
H. Song ◽  
C. Wei
Keyword(s):  
Growth Factor ◽  
Cyclosporine A ◽  
Transforming Growth Factor Beta ◽  
Renal Cell ◽  
Transforming Growth Factor ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Cellular Apoptosis ◽  
Growth Factor Beta ◽  
Renal Tubular

Cyclosporine-A (CsA) is the widely used immunosuppressant drug in renal transplantation. However, the effects of cyclosporine-A are limited by a significant nephrotoxicity. The mechanisms of CsA-induced allograft nephropathy are remaining controversial. Recent study indicated that cellular apoptosis may contribute to the cyclosporine A-mediated cytotoxic action. To date, regarding the effects of cyclosporine A on renal cell apoptosis-related gene expression remain poorly defined. p53 is an important gene in control of renal cell growth and death. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that has anti-proliferative as well as fibrogenic properties.We hypothesized that cyclosporine-A may increase p53 and TGF-β expression in renal tubular cells. These actions of cyclosporine-A may contribute to the cellular apoptosis, fibrosis and CsA-induced nephrotoxicity. Therefore, current study was designed to determine the effects of cyclosporine-A on the p53 and TGF-βl protein expression by immunohistochemical staining (IHCS) in cultured human tubular cells.

scholarly journals Palmitate aggravates proteinuria-induced cell death and inflammation via CD36-inflammasome axis in the proximal tubular cells of obese mice

2018 ◽  
Vol 315 (6) ◽  
pp. F1720-F1731 ◽  
Author(s):  
Lung-Chih Li ◽  
Jenq-Lin Yang ◽  
Wen-Chin Lee ◽  
Jin-Bor Chen ◽  
Chien-Te Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Tubular Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Caspase 1 ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Nlrp3 Inflammasomes

High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo- N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy.

scholarly journals Caspofungin is less nephrotoxic than amphotericin B in vitro and predominantly damages distal renal tubular cells

2005 ◽  
Vol 20 (10) ◽  
pp. 2071-2079 ◽  
Author(s):  
Binytha Wegner ◽  
Patrick Baer ◽  
Stefan Gauer ◽  
Gerhard Oremek ◽  
Ingeborg A. Hauser ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular
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