Novel Mechanisms of Cadmium-Induced Toxicity in Renal Cells

  • Jin-Yong Lee
  • Maki Tokumoto
  • Masahiko SatohEmail author
Part of the Current Topics in Environmental Health and Preventive Medicine book series (CTEHPM)


Cadmium (Cd) is an important industrial agent but is also an environmental pollutant that causes kidney disease. Chronic exposure to Cd results in its accumulation in proximal tubular cells of the kidney. This causes a variety of toxic effects that result in renal cell death. Current evidence indicates early phases of Cd-induced renal injury; for example, before renal cell death, Cd induces disruption to the transcription of apoptotic-related genes, dysregulation of autophagy, disruption of cell junction protein complexes, and accumulation of polyubiquitinated proteins. In this review, we discuss novel factors involved in Cd renal toxicity. This review may provide new insights for further elucidation of the mechanisms underlying Cd-induced toxicity in renal cells.


Cadmium Kidney injury Apoptosis Autophagy Cell-cell junction Ubiquitination 



This work was supported by the Study of the Health Effects of Heavy Metals, organized by the Ministry of the Environment, Japan.

Conflict of Interest Statement

The authors declare that they have no conflict of interest.


  1. 1.
    Akesson A, Barregard L, Bergdahl IA, Nordberg GF, Nordberg M, Skerfving S. Non-renal effects and the risk assessment of environmental cadmium exposure. Environ Health Perspect. 2014;122(5):431–8.CrossRefGoogle Scholar
  2. 2.
    Jarup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol. 2009;238(3):201–8.CrossRefGoogle Scholar
  3. 3.
    Nordberg GF, Nogawa K, Nordberg M, Friberg LT. Cadmium. In: Nordberg GF, Fowler BA, Nordberg M, Friberg LT, editors. Handbook on the toxicology of metals. 3rd ed. Amsterdam and Boston: Academic Press/Elsevier; 2007. p. 445–86.CrossRefGoogle Scholar
  4. 4.
    Bork U, Lee WK, Kuchler A, Dittmar T, Thevenod F. Cadmium-induced DNA damage triggers G(2)/M arrest via chk1/2 and cdc2 in p53-deficient kidney proximal tubule cells. Am J Physiol Renal Physiol. 2010;298(2):F255–65.CrossRefGoogle Scholar
  5. 5.
    Gao D, Xu Z, Zhang X, Zhu C, Wang Y, Min W. Cadmium triggers kidney cell apoptosis of purse red common carp (Cyprinuscarpio) without caspase-8 activation. Dev Comp Immunol. 2013;41(4):728–37.CrossRefGoogle Scholar
  6. 6.
    Nair AR, Lee WK, Smeets K, Swennen Q, Sanchez A, Thevenod F, Cuypers A. Glutathione and mitochondria determine acute defense responses and adaptive processes in cadmium-induced oxidative stress and toxicity of the kidney. Arch Toxicol. 2015;89(12):2273–89.CrossRefGoogle Scholar
  7. 7.
    Fujiki K, Inamura H, Matsuoka M. Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells. Cell Death Dis. 2014;5:e1378.CrossRefGoogle Scholar
  8. 8.
    Lee JY, Tokumoto M, Fujiwara Y, Satoh M. Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells. J Toxicol Sci. 2015;40(6):901–8.CrossRefGoogle Scholar
  9. 9.
    Lee JY, Tokumoto M, Hwang GW, Lee MY, Satoh M. Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity. Sci Rep. 2017;7:17287.Google Scholar
  10. 10.
    Fujiwara Y, Lee JY, Tokumoto M, Satoh M. Cadmium renal toxicity via apoptotic pathways. Biol Pharm Bull. 2012;35(11):1892–7.CrossRefGoogle Scholar
  11. 11.
    Aimola P, Carmignani M, Volpe AR, Di Benedetto A, Claudio L, Waalkes MP, et al. Cadmium induces p53-dependent apoptosis in human prostate epithelial cells. PLoS One. 2012;7(3):e33647.CrossRefGoogle Scholar
  12. 12.
    Son YO, Lee JC, Hitron JA, Pan J, Zhang Z, Shi X. Cadmium induces intracellular Ca2+- and H2O2-dependent apoptosis through JNK- and p53-mediated pathways in skin epidermal cell line. Toxicol Sci. 2010;113(1):127–37.CrossRefGoogle Scholar
  13. 13.
    Lee JY, Tokumoto M, Fujiwara Y, Hasegawa T, Seko Y, Shimada A, Satoh M. Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity. Sci Rep. 2016;6:21968.CrossRefGoogle Scholar
  14. 14.
    Tokumoto M, Fujiwara Y, Shimada A, Hasegawa T, Seko Y, Nagase H, Satoh M. Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo. J Toxicol Sci. 2011;36(2):191–200.CrossRefGoogle Scholar
  15. 15.
    Lee JY, Tokumoto M, Hattori Y, Fujiwara Y, Shimada A, Satoh M. Different Regulation of p53 Expression by cadmium exposure in kidney, liver, intestine, vasculature, and brain astrocytes. Toxicol Res. 2016;32(1):73–80.CrossRefGoogle Scholar
  16. 16.
    Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41.CrossRefGoogle Scholar
  17. 17.
    Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.CrossRefGoogle Scholar
  18. 18.
    Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–5.CrossRefGoogle Scholar
  19. 19.
    Sureshbabu A, Ryter SW, Choi ME. Oxidative stress and autophagy: crucial modulators of kidney injury. Redox Biol. 2015;4:208–14.CrossRefGoogle Scholar
  20. 20.
    Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem. 2006;281(40):30299–304.CrossRefGoogle Scholar
  21. 21.
    Luo B, Lin Y, Jiang S, Huang L, Yao H, Zhuang Q, et al. Endoplasmic reticulum stress eIF2alpha-ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney. Cell Death Dis. 2016;7(6):e2251.CrossRefGoogle Scholar
  22. 22.
    Wang SH, Shih YL, Ko WC, Wei YH, Shih CM. Cadmium-induced autophagy and apoptosis are mediated by a calcium signaling pathway. Cell Mol Life Sci. 2008;65(22):3640–52.CrossRefGoogle Scholar
  23. 23.
    Ogier-Denis E, Pattingre S, El Benna J, Codogno P. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem. 2000;275(50):39090–5.CrossRefGoogle Scholar
  24. 24.
    vom Dahl S, Dombrowski F, Schmitt M, Schliess F, Pfeifer U, Haussinger D. Cell hydration controls autophagosome formation in rat liver in a microtubule-dependent way downstream from p38MAPK activation. Biochem J. 2001;354(Pt 1):31–6.CrossRefGoogle Scholar
  25. 25.
    Liu F, Wang XY, Zhou XP, Liu ZP, Song XB, Wang ZY, Wang L. Cadmium disrupts autophagic flux by inhibiting cytosolic Ca2+-dependent autophagosome-lysosome fusion in primary rat proximal tubular cells. Toxicology. 2017;383:13–23.CrossRefGoogle Scholar
  26. 26.
    Lu Y, Dong S, Hao B, Li C, Zhu K, Guo W, et al. Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A. Autophagy. 2014;10(11):1895–905.CrossRefGoogle Scholar
  27. 27.
    Chua CE, Gan BQ, Tang BL. Involvement of members of the Rab family and related small GTPases in autophagosome formation and maturation. Cell Mol Life Sci. 2011;68(20):3349–58.CrossRefGoogle Scholar
  28. 28.
    Gutierrez MG, Munafo DB, Beron W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117(Pt 13):2687–97.CrossRefGoogle Scholar
  29. 29.
    Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000;406(6791):86–90.CrossRefGoogle Scholar
  30. 30.
    Forde JE, Dale TC. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci. 2007;64(15):1930–44.CrossRefGoogle Scholar
  31. 31.
    Wang SH, Shih YL, Kuo TC, Ko WC, Shih CM. Cadmium toxicity toward autophagy through ROS-activated GSK-3beta in mesangial cells. Toxicol Sci. 2009;108(1):124–31.CrossRefGoogle Scholar
  32. 32.
    Pizarro JG, Yeste-Velasco M, Rimbau V, Casadesus G, Smith MA, Pallas M, et al. Neuroprotective effects of SB-415286 on hydrogen peroxide-induced cell death in B65 rat neuroblastoma cells and neurons. Int J Dev Neurosci. 2008;26(3–4):269–76.CrossRefGoogle Scholar
  33. 33.
    Chakraborty PK, Lee WK, Molitor M, Wolff NA, Thevenod F. Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells. Mol Cancer. 2010;9:102.CrossRefGoogle Scholar
  34. 34.
    Prozialeck WC, Lamar PC, Lynch SM. Cadmium alters the localization of N-cadherin, E-cadherin, and beta-catenin in the proximal tubule epithelium. Toxicol Appl Pharmacol. 2003;189(3):180–95.CrossRefGoogle Scholar
  35. 35.
    Nollet F, Kools P, van Roy F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol. 2000;299(3):551–72.CrossRefGoogle Scholar
  36. 36.
    Adams CL, Nelson WJ. Cytomechanics of cadherin-mediated cell-cell adhesion. Curr Opin Cell Biol. 1998;10(5):572–7.CrossRefGoogle Scholar
  37. 37.
    Lutz KL, Siahaan TJ. Molecular structure of the apical junction complex and its contribution to the paracellular barrier. J Pharm Sci. 1997;86(9):977–84.CrossRefGoogle Scholar
  38. 38.
    Leussink BT, Litvinov SV, de Heer E, Slikkerveer A, van der Voet GB, Bruijn JA, de Wolff FA. Loss of homotypic epithelial cell adhesion by selective N-cadherin displacement in bismuth nephrotoxicity. Toxicol Appl Pharmacol. 2001;175(1):54–9.CrossRefGoogle Scholar
  39. 39.
    Lee JY, Tokumoto M, Hwang GW, Satoh M. Cadmium-induced protein ubiquitination in UBA80 knockdown HK-2 cells. Fundam Toxicol Sci. 2016;3(6):281–4.CrossRefGoogle Scholar
  40. 40.
    Tokumoto M, Lee JY, Fujiwara Y, Satoh M. DNA microarray expression analysis of mouse kidney following cadmium exposure for 12 months. J Toxicol Sci. 2013;38(5):799–802.CrossRefGoogle Scholar
  41. 41.
    Tokumoto M, Ohtsu T, Honda A, Fujiwara Y, Nagase H, Satoh M. DNA microarray analysis of normal rat kidney epithelial cells treated with cadmium. J Toxicol Sci. 2011;36(1):127–9.CrossRefGoogle Scholar
  42. 42.
    Uekusa H, Namimatsu M, Hiwatashi Y, Akimoto T, Nishida T, Takahashi S, Takahashi Y. Cadmium interferes with the degradation of ATF5 via a post-ubiquitination step of the proteasome degradation pathway. Biochem Biophys Res Commun. 2009;380(3):673–8.CrossRefGoogle Scholar
  43. 43.
    Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol. 2008;9(9):679–90.CrossRefGoogle Scholar
  44. 44.
    Baker RT, Board PG. The human ubiquitin-52 amino acid fusion protein gene shares several structural features with mammalian ribosomal protein genes. Nucleic Acids Res. 1991;19(5):1035–40.CrossRefGoogle Scholar
  45. 45.
    Lee JY, Tokumoto M, Fujiwara Y, Lee MY, Satoh M. Effects of cadmium on the gene expression of SLC39A1 coding for ZIP1 protein. Fundam Toxicol Sci. 2014;1(4):131–3.CrossRefGoogle Scholar
  46. 46.
    Lee JY, Tokumoto M, Fujiwara Y, Lee MY, Satoh M. The involvement of GPRC5B in cadmium toxicity in HK-2 cells. Fundam Toxicol Sci. 2014;1(4):165–7.CrossRefGoogle Scholar
  47. 47.
    Lee JY, Tokumoto M, Satoh M. The enhancement effect of HIST1H4C knockdown on cadmium toxicity in human proximal tubular cells. Fundam Toxicol Sci. 2015;2(6):259–62.CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Laboratory of Pharmaceutical Health Sciences, School of PharmacyAichi Gakuin UniversityNagoyaJapan

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