Prolonged Endoplasmic Reticulum Stress Induces Apoptotic Cell Death in an Experimental Model of Chronic Cyclosporine Nephropathy

Han, Sang Woo; Li, Can; Ahn, Kyung Ohk; Lim, Sun Woo; Song, Hyun Guk; Jang, Yoon Suk; Cho, Yoon Mi; Jang, Young Min; Ghee, Jung Yeon; Kim, Jin Young; Kim, Su Hyun; Kim, Jin; Kwon, Oh Joo; Yang, Chul Woo

doi:10.1159/000127432

Cited by 63 publications

(40 citation statements)

References 41 publications

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“…CsA treatment dramatically induced CCN as shown by interstitial inflammatory infiltration, renal tubular injury and fibrosis in renal tissue. CsA treatment decreased kidney function and increased both tubular and interstitial cell apoptosis in different animals [11,12,13,14,15]. Renal cell apoptosis was identified by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in all studies and various in situ apoptosis detection kits were used.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Xiao

Shan

et al. 2012

Am J Nephrol

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Background/Aims: Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is an important cause of chronic renal dysfunction with no effective clinical intervention. To further elucidate the mechanisms of renal cell apoptosis in CCN, all relevant in vivo studies on this subject were analyzed. Methods: We searched for in vivo studies on the mechanisms of CsA-induced renal cell apoptosis in Medline (1966–July 2010), Embase (1980–July 2010) and ISI (1986–July 2010). The studies were evaluated for their quality according to a set of in vivo standards, data extracted according to PICOS, and then synthesized. Results: Renal cell apoptosis was an important feature of CCN and an important factor of renal dysfunction. First, CsA could upregulate Fas/Fas ligand, downregulate Bcl-2/Bcl-XL, and increase caspase-1 and caspase-3. Second, it could induce oxidative stress and damage the antioxidant defense system. Third, it could increase endoplasmic reticulum stress protein in a dose- and time-dependent manner. Fourth, CsA could impair the urine concentration and decrease the expression of hypertonicity-induced genes. Fifth, CsA-induced renal cell apoptosis was significantly decreased by blocking the angiotensin II type 1 receptor using losartan. Conclusions: The in vivo mechanisms for CCN are more complex than those found in vitro. CsA can induce renal cell apoptosis using five pathways in vivo and activated caspases might be the ultimate intersection of these pathways and the common intracellular pathway mediating apoptosis. These data provide new potential points for intervention and need to be confirmed by further studies.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Xiao

Shan

et al. 2012

Am J Nephrol

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“…ER stress has recently been associated with the pathogenesis of Alzheimer's disease [18], Parkinson's disease [19] and several renal disorders [7,20,21]. GRP78 and GRP94 are key ER regulatory proteins that function as molecular chaperones and play an important role in the recognition of unfolded proteins [22].…”

Section: Discussionmentioning

confidence: 99%

“…ER stress has recently been found to be involved in some renal diseases [6,7,8]. As Aldo-induced renal injury is known to be accompanied by oxidative stress and heavy proteinuria, factors which are known to induce ER stress, we hypothesized that Aldo-induced renal injury may be accompanied by increased ER stress, which may contribute to the pathogenesis of renal injury.…”

Section: Introductionmentioning

confidence: 99%

Contributions of Endoplasmic Reticulum Stress and Reactive Oxygen Species to Renal Injury in Aldosterone/Salt-Induced Rats

Cheng

Ding²,

Yang³

et al. 2014

Nephron Exp Nephrol

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Background: Recent studies have suggested that aldosterone (Aldo) plays a key role in the pathogenesis of renal injury; however, the molecular mechanisms of Aldo-induced renal injury have not been characterized. This study was performed to test the hypothesis that reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress contribute to the pathogenesis of Aldo- and salt-induced renal injury. Methods: Rats were uninephrectomized and treated with one of the following for 4 weeks: (1) vehicle, (2) vehicle + NaCl, (3) Aldo + NaCl or (4) Aldo + NaCl + N-acetyl-L-cysteine (NAC). Following this treatment period, the extent of renal injury was assessed by periodic acid-Schiff staining and immunohistochemistry, and the expression levels of proteins related to ER stress, as well as p47phox and p67phox in the kidney, were measured by Western blot. Intracellular ROS generation was evaluated by 2′7′-dichlorofluorescin diacetate fluorescence and ELISA kits. Results: Rats that received Aldo + 1% NaCl exhibited severe renal injury. ROS levels were higher in Aldo-infused rats and were inhibited by NAC. Renal cortical protein levels of GRP78, GRP94, CHOP, ATF-4, p47phox and p67phox were significantly upregulated in rats that received Aldo + 1% NaCl. Treatment with NAC significantly ameliorated the increase in the expression of these proteins. Conclusion: These data suggest that ROS and ER stress play a role in the progression of Aldo- and salt-induced renal injury.

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“…Prolonged CHOP expression, which has been associated with induction of apoptosis in vitro and in vivo (13,38), may require toxin enzymatic activity. Thus, ongoing generation of truncated and/or misfolded host proteins may be necessary for signaling leading to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 Regulates the Onset of Shiga Toxin 1-Induced Apoptosis in THP-1 Cells

et al. 2009

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Shiga toxins (Stxs), which are proteins expressed by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli, are potent protein synthesis inhibitors. Stx-producing organisms cause bloody diarrhea with the potential to progress to acute renal failure and central nervous system complications. Studies using animal models of these diseases have shown that Stxs are major virulence factors, and purified toxins have been shown to be capable of killing many types of cells in vitro. We showed that Stx type 1 (Stx1) rapidly induced apoptosis in undifferentiated, monocytic THP-1 cells through a mechanism involving the endoplasmic reticulum (ER) stress response. Rapid apoptosis correlated with increased expression of C/EBP homologous protein (CHOP), TRAIL, and DR5, while expression of the antiapoptotic factor Bcl-2 was downregulated. Stx1 treatment of differentiated, macrophage-like THP-1 cells was associated with cytokine production and delayed apoptosis. The mechanisms contributing to cell maturation-dependent differences in responses to Stx1 are unknown. We show here that in macrophage-like cells, Stx1 activated the proximal ER stress sensors RNA-dependent protein kinase-like ER kinase and inositol-requiring ER signal kinase 1␣ but did not activate activating transcription factor 6. Proapoptotic signaling pathways mediated by CHOP and by Bax and Bak were activated by Stx1. However, the toxin also activated prosurvival signaling through increased expression, mitochondrial translocation, and alternative phosphorylation of Bcl-2.Shiga toxins (Stxs), also called Shiga-like toxins or verotoxins, are potent protein synthesis inhibitors expressed by the enteric pathogens Shigella dysenteriae (serotype 1) and Escherichia coli (select serotypes). Stxs act as virulence factors by increasing the severity of bloody diarrhea and increasing the likelihood of development of life-threatening postdiarrheal sequelae, such as acute renal failure (hemolytic-uremic syndrome) and central nervous system complications (40). S. dysenteriae serotype 1 expresses the prototypic Stx, while closely related toxins expressed by E. coli can be classified into Stx type 1 (Stx1) and Stx2 (30). X-ray crystallographic analyses revealed that all Stxs contain six protein subunits in an arrangement described as an AB 5 structure. Stx A-subunits possess N-glycosidase activity that depurinates a specific unpaired adenine residue from eukaryotic rRNA, leading to protein synthesis inhibition in the intoxicated cell (11,35). The pentameric Bsubunits are responsible for toxin binding to the cell surface and interact with the neutral globo series glycolipid globotriaosylceramide (for a review, see reference 26). Toxin-mediated receptor cross-linking through interaction with the pentameric

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Prolonged Endoplasmic Reticulum Stress Induces Apoptotic Cell Death in an Experimental Model of Chronic Cyclosporine Nephropathy

Cited by 63 publications

References 41 publications

Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Mechanisms of Cyclosporine-Induced Renal Cell Apoptosis: A Systematic Review

Contributions of Endoplasmic Reticulum Stress and Reactive Oxygen Species to Renal Injury in Aldosterone/Salt-Induced Rats

Bcl-2 Regulates the Onset of Shiga Toxin 1-Induced Apoptosis in THP-1 Cells

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