Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway

Nilesh M. Kalariya, Nancy K. Wills, Kota V. Ramana, Satish K. Srivastava, Frederik J G M van Kuijk

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47 Scopus citations


Cadmium (Cd), released from cigarette smoke and metal industrial activities, is known to accumulate in human body organs including retina and is particularly higher in retinal tissues of age-related macular degeneration (AMD) eyes compared to non-AMD eyes. We have determined the cytotoxic effects of Cd on human retinal pigment epithelial (RPE) cells. Upon Cd treatment, there was a dose- and time-dependent decline in ARPE-19 cell viability as well as early apoptotic changes such as altered mitochondrial membrane potential (MMP) and Cytochrome C release in cytosol. Depletion of GSH by buthionine-[S,R]-sulfoximine (BSO) resulted in increased Cd toxicity in ARPE-19 cells. Cadmium also caused reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinases (MAPKs) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (Erk1/2), and p38 in ARPE-19 cells. Antioxidants such as N-acetylcysteine (NAC) significantly reduced Cd-induced toxicity. These results indicate that elevated ROS-induced activation of the MAPK signaling pathway could be associated with Cd-induced RPE cell apoptosis, one of the major contributing factors in AMD. The toxic effects of Cd on ARPE-19 cells indicate that environmental heavy metals such as Cd could be important potential factors in RPE cells death associated retinal diseases particularly related to smoking.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
JournalExperimental Eye Research
Issue number4
StatePublished - Oct 2009

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Grants GM71036 (to K.V.R.), DK36118 (to S.K.S.), and Philip Morris Fund (N.W.), Wilkins AMD Fund as well as Research to Prevent Blindness (to FJGMvK).


  • AMD
  • MAPK
  • apoptosis
  • cadmium
  • oxidative stress
  • retinal pigment epithelium

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