Skip to main content
Log in

The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Cadmium preferentially accumulates in the kidney, the major target for cadmium-related toxicity. Several underlying mechanisms are postulated, and reactive oxygen species (ROS) have been considered as crucial mediators for tissue injuries. In addition to oxidative stress, we recently disclosed that endoplasmic reticulum (ER) stress also plays a critical role. Cadmium causes ER stress in vitro and in vivo and mediates induction of apoptosis in target tissues. In this article, we describe a role for ER stress and involvement of particular branches of the unfolded protein response (UPR) in cadmium-triggered tissue injury, especially nephrotoxicity. We also discuss relationship between oxidative stress and ER stress, and involvement of selective ROS in the induction of pro-apoptotic branches of the UPR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Bernard A (2004) Renal dysfunction induced by cadmium: biomarkers of critical effects. Biometals 17:519–523

    Article  CAS  Google Scholar 

  • Biagioli M, Pifferi S, Ragghianti M, Bucci S, Rizzuto R, Pinton P (2008) Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium 43:184–195

    Article  CAS  Google Scholar 

  • Brasier AR, Ron D, Tate JE, Habener JF (1990) A family of constitutive C/EBP-like DNA binding proteins attenuate the IL-1α induced, NF-κB mediated trans-activation of the angiotensinogen gene acute-phase response element. EMBO J 9:3933–3944

    CAS  Google Scholar 

  • Buttke TM, Sandstromb PA (1994) Oxidative stress as a mediator of apoptosis. Immunol Today 15:7–10

    Article  CAS  Google Scholar 

  • Chaudhuri TK, Paul S (2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J 273:1331–1349

    Article  CAS  Google Scholar 

  • Chun HS, Lee H, Son JH (2001) Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741. Neurosci Lett 316:5–8

    Article  CAS  Google Scholar 

  • Du S, Hiramatsu N, Hayakawa K, Kasai A, Okamura M, Huang T, Yao J, Takeda M, Araki I, Sawada N, Paton AW, Paton JC, Kitamura M (2009) Suppression of NF-κB by cyclosporine A and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response. J Immunol 182:7201–7211

    Article  CAS  Google Scholar 

  • Friberg L, Elinder CG, Kjellstrom T, Nordberg GF (1986) Cadmium and health: a toxicological and epidemiological approach, vol 1, 2. CRC Press, Boca Raton

    Google Scholar 

  • Gennari A, Cortese E, Boveri M, Casado J, Prieto P (2003) Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells. Toxicology 183:211–220

    Article  CAS  Google Scholar 

  • Gotoh T, Oyadomari S, Mori K, Mori M (2002) Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem 277:12343–12350

    Article  CAS  Google Scholar 

  • Hamada T, Nakano S, Iwai S, Tanimoto A, Ariyoshi K, Koide O (1991) Pathological study on beagles after long-term oral administration of cadmium. Toxicol Pathol 19:138–147

    Article  CAS  Google Scholar 

  • Harama D, Koyama K, Mukai M, Shimokawa N, Miyata M, Nakamura Y, Ohnuma Y, Ogawa H, Matsuoka S, Paton AW, Paton JC, Kitamura M, Nakao A (2009) A sub-cytotoxic dose of subtilize cytotoxin prevents LPS-induced inflammatory responses, depending on its capacity to induce the unfolded protein response. J Immunol 183:1368–1374

    Article  CAS  Google Scholar 

  • Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  CAS  Google Scholar 

  • Hayakawa K, Hiramatsu N, Okamura M, Yao J, Paton AW, Paton JC, Kitamura M (2008) Blunted activation of NF-κB and NF-κB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response. Biochem Biophys Res Commun 365:47–53

    Article  CAS  Google Scholar 

  • Hayakawa K, Hiramatsu N, Okamura M, Yamazaki H, Nakajima S, Yao J, Paton AW, Paton JC, Kitamura M (2009) Acquisition of anergy to proinflammatory cytokines in non-immune cells through endoplasmic reticulum stress response: a mechanism for subsidence of inflammation. J Immunol 182:1182–1191

    CAS  Google Scholar 

  • Hayakawa K, Nakajima S, Hiramatsu N, Okamura M, Huang T, Saito Y, Tagawa Y, Tamai M, Takahashi S, Yao J, Kitamura M (2010) ER stress depresses NF-κB activation in mesangial cells through preferential induction of C/EBPβ. J Am Soc Nephrol 21:73–81

    Article  CAS  Google Scholar 

  • Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776

    Article  CAS  Google Scholar 

  • Hiramatsu N, Kasai A, Hayakawa K, Yao J, Kitamura M (2006) Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: evidence for systemic, transient ER stress during endotoxemia. Nucleic Acids Res 34:e93

    Article  Google Scholar 

  • Hiramatsu N, Kasai A, Du S, Takeda M, Hayakawa K, Okamura M, Yao J, Kitamura M (2007) Rapid, transient induction of ER stress in the liver and kidney after acute exposure to heavy metal: evidence from transgenic sensor mice. FEBS Lett 581:2055–2059

    Article  CAS  Google Scholar 

  • Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor-α links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084

    Article  CAS  Google Scholar 

  • Ishido M, Homma-Takeda S, Tohyama C, Suzuki T (1998) Apoptosis in rat renal proximal tubular cells induced by cadmium. J Toxicol Environ Health A 55:1–12

    Article  CAS  Google Scholar 

  • Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trends Biochem Sci 21:83–86

    CAS  Google Scholar 

  • Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208

    Article  Google Scholar 

  • Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11:5–13

    Article  CAS  Google Scholar 

  • Kitamura M (2008) Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: janus faces. Am J Physiol Renal 295:F323–F342

    Article  CAS  Google Scholar 

  • Kitamura M (2009) Biphasic, bidirectional regulation of NF-κB by endoplasmic reticulum stress. Antioxid Redox Signal 11:2353–2364

    Article  CAS  Google Scholar 

  • Kwon OY, Kim YJ, Choi Y, Kim H, Song C, Shong M (1999) The endoplasmic reticulum chaperone GRP94 is induced in the thyrocytes by cadmium. Z Naturforsch C 54:573–577

    CAS  Google Scholar 

  • Lee AS (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26:504–510

    Article  CAS  Google Scholar 

  • Lind Y, Engman J, Jorhem L, Glynn AW (1997) Cadmium accumulation in liver and kidney of mice exposed to the same weekly cadmium dose continuously or once a week. Food Chem Toxicol 35:891–895

    Article  CAS  Google Scholar 

  • Liu F, Inageda K, Nishitai G, Matsuoka M (2006) Cadmium induces the expression of Grp78, an endoplasmic reticulum molecular chaperone, in LLC-PK1 renal epithelial cells. Environ Health Perspect 114:859–864

    Article  CAS  Google Scholar 

  • Liu J, Qian SY, Guo Q, Jiang J, Waalkes MP, Mason RP, Kadiiska MB (2008) Cadmium generates reactive oxygen- and carbon-centered radical species in rats: insights from in vivo spin-trapping studies. Free Radic Biol Med 45:475–481

    Article  CAS  Google Scholar 

  • Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238:209–214

    Article  CAS  Google Scholar 

  • Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–22793

    Article  CAS  Google Scholar 

  • McKnight SL (2001) McBindall: a better name for CCAAT/enhancer binding proteins? Cell 107:259–261

    Article  CAS  Google Scholar 

  • Nogawa K (1981) Itai–itai disease and follow-up studies. In: Nriagu JO (ed) Cadmium in the environment. Wiley, New York, pp 1–37

    Google Scholar 

  • Okamura M, Takano Y, Hiramatsu N, Hayakawa K, Yao J, Paton AW, Paton JC, Kitamura M (2008) Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response. Am J Physiol Renal Physiol 295:F1495–F1503

    Article  CAS  Google Scholar 

  • Organization World Health (1992) Cadmium. Environmental health criteria. World Health Organization, Geneva

    Google Scholar 

  • Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    Article  Google Scholar 

  • Pahl HL, Baeuerle PA (1995) A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-κB. EMBO J 14:2580–2588

    CAS  Google Scholar 

  • Pourova J, Kottova M, Voprsalova M, Pour M (2010) Reactive oxygen and nitrogen species in normal physiological processes. Acta Physiol (Oxf) 198:15–35

    Article  CAS  Google Scholar 

  • Prozialeck WC, Lamar PC (1995) Effects of glutathione depletion on the cytotoxic actions of cadmium in LLC-PK1 cells. Toxicol Appl Pharmacol 134:285–295

    Article  CAS  Google Scholar 

  • Qian Y, Falahatpisheh MH, Zheng Y, Ramos KS, Tiffany-Castiglioni E (2001) Induction of 78 kD glucose-regulated protein (GRP78) expression and redox-regulated transcription factor activity by lead and mercury in C6 rat glioma cells. Neurotox Res 3:581–589

    Article  CAS  Google Scholar 

  • Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ (2003) Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci USA 100:6087–6092

    Article  CAS  Google Scholar 

  • Sekine Y, Takeda K, Ichijo H (2006) The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med 6:87–97

    Article  CAS  Google Scholar 

  • Stein B, Cogswell PC, Baldwin AS Jr (1993) Functional and physical associations between NF-κB and C/EBP family members: a Rel domain—bZIP interaction. Mol Cell Biol 13:3964–3974

    CAS  Google Scholar 

  • Szabo C, Ohshima H (1997) DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide 1:373–385

    Article  CAS  Google Scholar 

  • Tagawa Y, Hiramatsu N, Kasai A, Hayakawa K, Okamura M, Yao J, Kitamura M (2008) Induction of apoptosis by cigarette smoke via ROS-dependent ER stress and CHOP. Free Radic Biol Med 45:50–59

    Article  CAS  Google Scholar 

  • Takano Y, Hiramatsu N, Okamura M, Hayakawa K, Shimada T, Kasai A, Yokouchi M, Shitamura A, Yao J, Paton AW, Paton JC, Kitamura M (2007) Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response. Biochem Biophys Res Commun 360:470–475

    Article  CAS  Google Scholar 

  • Tchounwou PB, Ishaque AB, Schneider J (2001) Cytotoxicity and transcriptional activation of stress genes in human liver carcinoma cells (HepG2) exposed to cadmium chloride. Mol Cell Biochem 222:21–28

    Article  CAS  Google Scholar 

  • Thevenod F (2003) Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93:87–93

    Article  Google Scholar 

  • Thevenod F, Friedmann JM, Katsen AD, Hauser IA (2000) Up-regulation of multidrug resistance P-glycoprotein via NF-κB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis. J Biol Chem 275:1887–1896

    Article  CAS  Google Scholar 

  • Timblin CR, Janssen YM, Goldberg JL, Mossman BT (1998) GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed to asbestos, cadmium, or H2O2. Free Radic Biol Med 24:632–642

    Article  CAS  Google Scholar 

  • Wang SH, Shih YL, Lee CC, Chen WL, Lin CJ, Lin YS, Wu KH, Shih CM (2009) The role of endoplasmic reticulum in cadmium-induced mesangial cell apoptosis. Chem Biol Interact 181:45–51

    Article  CAS  Google Scholar 

  • Weber M, Sydlik C, Quirling M, Nothdurfter C, Zwergal A, Heiss P, Bell S, Neumeier D, Ziegler-Heitbrock HWL, Brand K (2003) Transcriptional inhibition of interleukin-8 expression in tumor necrosis factor-tolerant cells: evidence for involvement of C/EBP. J Biol Chem 278:23586–23593

    Article  CAS  Google Scholar 

  • Wu J, Kaufman RJ (2006) From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ 13:374–384

    Article  CAS  Google Scholar 

  • Xie J, Shaikh ZA (2006) Cadmium-induced apoptosis in rat kidney epithelial cells involves modulation of NF-κB activity. Toxicol Sci 224:56–65

    Article  CAS  Google Scholar 

  • Xie Z, Zhang Y, Li A, Li P, Ji W, Huang D (2010) Cd-induced apoptosis was mediated by the release of Ca2+ from intracellular Ca storage.Toxicol Lett 192:115–118

    Article  CAS  Google Scholar 

  • Xue X, Piao JH, Nakajima A, Sakon-Komazawa S, Kojima Y, Mori K, Yagita H, Okumura K, Harding H, Nakano H (2005) Tumor necrosis factor-α (TNF-α) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNF-α. J Biol Chem 280:33917–33925

    Article  CAS  Google Scholar 

  • Yeh JH, Huang CC, Yeh MY, Wang JS, Lee JK, Jan CR (2009) Cadmium-induced cytosolic Ca2+ elevation and subsequent apoptosis in renal tubular cells. Basic Clin Pharmacol Toxicol 104:345–351

    Article  CAS  Google Scholar 

  • Yokouchi M, Hiramatsu N, Hayakawa K, Kasai A, Takano Y, Yao J, Kitamura M (2007) Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response. Cell Death Differ 14:1467–1474

    Article  CAS  Google Scholar 

  • Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, Kasai A, Takano Y, Shitamura A, Shimada T, Yao J, Kitamura M (2008) Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem 283:4252–4260

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masanori Kitamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kitamura, M., Hiramatsu, N. The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity. Biometals 23, 941–950 (2010). https://doi.org/10.1007/s10534-010-9296-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-010-9296-2

Keywords

Navigation