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EDITORIAL FOCUS
Experimentelle Nephrologie, Medizinische Klinik and Poliklinik D, Universitätsklinikum Münster, Münster, Germany
CADMIUM (Cd2+) is a nonessential heavy metal that is known as an important industrial and environmental pollutant. In industrialized countries the Cd2+ burden on the environment has generally declined, once it became clear that Cd2+ represents a dangerous health hazard. This reduction of Cd2+ pollution occurred partly because industry renounced the use of Cd2+ for production but also because the Cd2+ manufacturing industry was transferred to emerging industrialized countries. In fact, globally Cd2+ pollution has increased, and in countries such as China and India Cd2+ pollution has grown to be a significant ecological problem.
Because Cd2+ has a long biological half-life (10–25 yr) and a low rate of excretion, the body becomes a "sink," and Cd2+ accumulates until a threshold is reached and causes toxicity to many vital organs including the lungs, liver, and kidneys. The S1 segment of the proximal tubules is particularly sensitive to Cd2+ toxic effects, because in this part of the nephron transport and receptor systems for both free and bound Cd2+ are present (2, 8). For this reason, nephrotoxicity induced by Cd2+ may result in a general transport defect of the proximal tubules, which is manifested by proteinuria, aminoaciduria, glucosuria, and phosphaturia and mimics the De Toni-Debré-Fanconi syndrome. Human studies indicate that 7% of the Cd2+-exposed population have renal dysfunction from Cd2+ exposure (3). The importance of an exact understanding of the cellular mechanisms involved in Cd2+ toxicity is therefore evident. Cd2+ modulates gene expression and signal transduction and reduces activities of proteins involved in antioxidant defenses (1). The cellular processes responsible for the development of nephrotoxicity culminate in triggering of cell death by either apoptosis or necrosis (7). Short exposure (3–6 h) to Cd2+ induces apoptotic cell death mediated by the Ca2+-dependent proteases calpains (4). This pathway is distinct from longer (12–24 h) exposures to Cd2+, where mitochondrial damage results, followed by release of proapoptotic factors and thus leading to activation of caspase proteases to induce cell death (4). A further aspect of cell death signaling is the cross talk between calpains and caspases. It has been shown that calpains have the capacity to activate the executioner caspase, caspase-3, in a concerted effort to induce a "more efficient" apoptotic cell death (4).
In the recent paper entitled "Cadmium-induced ceramide formation triggers calpain-dependent apoptosis in cultured kidney proximal tubule cells" (6), Lee and colleagues describe the upstream processes underlying calpain-induced apoptosis caused by Cd2+. These are the most recent data that add to the ever-increasing knowledge about Cd2+-induced cell death pathways, which has been substantially generated through previous work by this group (4, 5, 7). Even though ceramides have long been known to be involved in apoptotic signaling pathways, Lee et al. (6) show for the first time that exposure of kidney proximal tubular cells to low micromolar Cd2+ concentrations induces ceramide generation already after 3 h. Inhibition of ceramide synthase by fumonisin B1 abolished Cd2+-induced ceramide formation after 3 h and also apoptosis after 3–6 h. According to these data, ceramide formation is attributed to a de novo synthesis pathway rather than to hydrolysis of the plasma membrane sphingomyelin. Since apoptosis at these time points involves calpain activation (4), the authors have investigated the hypothesis of whether ceramide formation and calpain activation are somehow connected. Indeed, it could be demonstrated that ceramide formation is a prerequisite for active calpains. But how do increased ceramide levels induce calpain activation? This question was answered through live Ca2+ imaging to monitor cytosolic Ca2+ concentration. Because of the Ca2+ dependence of calpains for activation, an increase in cytosolic Ca2+ was expected. By applying exogenous cell-permeant C6-ceramide to fura-2-loaded cells, Lee et al. could show that cytosolic Ca2+ rapidly increases after application of C6-ceramide, suggesting that ceramide stimulates calpain activity by increasing cytosolic Ca2+.
A further interesting observation, as well as corroboration of the ceramide-calpain-caspase connection, came from a series of experiments using C6-ceramide. Maximal cell death by C6-ceramide was found to be significantly different after 24-h exposure compared with exposure for 3–6 h. The authors hypothesized the involvement of caspases since they were found to be activated by Cd2+ after 24 h only (4). In fact, the presence of a caspase-3 inhibitor, z-DEVD-fmk, attenuated C6-ceramide-induced cell death at 24 h, demonstrating partial caspase dependence in the propagation of cell death by ceramide.
To summarize, an early apoptotic signaling pathway induced by Cd2+ can be linked to late-onset signals by calpain activation.
This paper greatly contributes to the understanding of the apoptotic signaling pathways induced by Cd2+, explaining the early events implicated in apoptotic cell death and putting them in relation to late-onset events. Considering the growing exposure of humans to Cd2+, this issue is of special importance, in view of possible therapeutic intervention to treat Cd2+ poisoning by blocking early stages of apoptosis.
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2. Bridges CC, Zalups RK. Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204: 274–308, 2005.[CrossRef][Web of Science][Medline]
3. Friberg L, Elinder CG, Kjellstrom T, Nordberg GF. Cadmium and Health: a Toxicological and Epidemiological Approach. Boca Raton, FL: CRC, 1986.
4. Lee WK, Abouhamed M, Thévenod F. Caspase-dependent and -independent pathways for cadmium-induced apoptosis in cultured kidney proximal tubule cells. Am J Physiol Renal Physiol 291: F823–F832, 2006.
5. Lee WK, Bork U, Gholamrezaei F, Thévenod F. Cd2+-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca2+ uniporter. Am J Physiol Renal Physiol 288: F27–F39, 2005.
6. Lee WK, Torchalski B, Thévenod F. Cadmium-induced ceramide formation triggers calpain-dependent apoptosis in cultured kidney proximal tubule cells. Am J Physiol Cell Physiol (June 27, 2007). doi:10.1152/ajpcell.00197.2007.
7. Thévenod F. Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93: 87–93, 2003.
8. Wolff NA, Abouhamed M, Verroust PJ, Thévenod F. Megalin-dependent internalization of cadmium-metallothionein and cytotoxicity in cultured renal proximal tubule cells. J Pharmacol Exp Ther 318: 782–791, 2006.
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