Multiple roles of cadmium in cell death and survival

Chemico-Biological Interactions 188 (2010) 267–275

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Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint

Mini-review

Multiple roles of cadmium in cell death and survival Douglas M. Templeton ∗ , Ying Liu Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, Canada

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Article history: Available online 27 March 2010 Keywords: Cadmium Carcinogenesis Apoptosis Autophagy Mesangial cell Kinase activation

a b s t r a c t Cadmium is a toxic metal with no known biological function. It is increasingly important as an environmental hazard to both humans and wildlife, and it exemplifies the double edged nature of many toxic substances. Thus, on the one hand cadmium can act as a mitogen, stimulate cell proliferation, inhibit apoptosis, inhibit DNA repair, and promote cancer in a number of tissues. On the other hand, it causes tissue damage, notably in the kidney, by inducing cell death. At low and moderate concentrations in cell culture systems (e.g., 0.1–10 ␮M) cadmium primarily causes apoptosis, and at higher concentrations (>50 ␮M) necrosis becomes evident. This generalization appears to hold in vivo. There is also evidence of cadmium-induced autophagy, although whether this is a direct cause of cell death remains uncertain. After discussing these generalities, this review considers the details of apoptotic death, and its inhibition, in renal mesangial cells. We also present evidence for the effect of environmental exposure to cadmium in affecting renal function, and in particular review the evidence for the role of the mesangial cell in cadmium nephrotoxicity. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cadmium as a carcinogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cadmium and cell proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cadmium and the kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cadmium-induced necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apoptotic-like cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kinases and apoptotic death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Cadmium is an occupationally and environmentally important toxic element that is present in air, soil, sediment, and water. Non-

Abbreviations: ACD, autophagic cell death; AIF, apoptosis-inducing factor; CaMK, Ca2+ /calmodulin-dependent protein kinase; EGFR, epidermal growth factor receptor; IARC, International Agency for Research on Cancer; MAPK, mitogen-activated protein kinase; PCD, programmed cell death; ROS, reactive oxygen species. ∗ Corresponding author at: Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building Rm. 6302, 1 King’s College Circle, Toronto M5S 1A8, Canada. Tel.: +1 416 978 3972; fax: +1 416 978 5959. E-mail address: [email protected] (D.M. Templeton). 0009-2797/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2010.03.040

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occupational exposure is mainly from the diet and smoking [1], with an estimated individual daily consumption of 30 ␮g in the USA, and considerably higher in China and Japan [2]. Cadmium accumulates in the human body with a long biological half-life of 2–3 decades. Its targets of toxicity include lung, liver, kidney, bone, the cardiovascular system, and the immune system [3–7], where cadmium-induced cell death leads to loss of function. However, cadmium also acts as a cancer promoter through mitogenic effects on gene expression (reviewed in [2,8]). It causes transformation in cultured cell lines [9,10] and produces malignant tumours in testes, prostate, lungs, pancreas and liver of experimental animals [4,11–13]. It is considered a human carcinogen by the International Agency for Research on Cancer (IARC) [14] and occupational expo-

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sure has been associated with cancers of lung and possibly prostate, kidney, and pancreas [11]. In addition to effects on gene expression and DNA repair, cadmium carcinogenesis probably involves inhibition of apoptosis [2,10,15]. In the 1980s, attention shifted from the obvious effects of cadmium in occupational health to recognition of cadmium as an important environmental problem, with epidemiological studies such as Cadmibel [16–19] focusing on the impact of low level exposures in industrialized regions. There is now recognition of widespread toxicity amongst wildlife [20]. Cadmium pollution arising from disposal of electronics components is of major environmental significance, especially in developing economies that accept and process electronic waste from industrialized countries. Evidence is mounting that environmental exposures are associated with cancers of the kidney, bladder, prostate, and endometrium [21]. Cadmium-induced cell death may be beneficial if it follows a mitogenic or mutagenic event, and inhibition of cell death by cadmium may contribute to the development of cancer. Here we will first discuss the mitogenic, proliferative, and anti-apoptotic effects of cadmium, and then consider how cadmium initiates divergent pathways of cell death.

2. Cadmium as a carcinogen While cadmium is recognized as a category 1 carcinogen by IARC [14], it is also realized that it is a weak mutagen and a poor initiator of cancer [11,22]. It interacts weakly with DNA and may act through epigenetic and (or) other mechanisms, including mitogenic effects on gene expression, inhibition of DNA repair, and inhibition of apoptosis [11]. Both oxidative stress and inhibition of repair of oxidative DNA damage undoubtedly play a role in cadmium carcinogenesis [23,24]. Although cadmium does not redox cycle and therefore does not directly promote Fenton chemistry, it nevertheless increases cellular levels of reactive oxygen species (ROS) [25,26]. Depletion of antioxidant defences might seem a plausible mechanism, but cadmium also facilitates adaptive increases in levels of glutathione, the cadmium-binding protein metallothionein, and catalase that are protective against peroxidative damage [24–28]. Displacement of Fenton-active metals from other sites and inhibition of mitochondrial electron transport are also plausible mechanisms [29]. Disruption of mitochondrial function itself may be a more important factor than ROS production in cadmium-induced cell death [26,30]. Cadmium-induced oxidative damage to thiol groups of a number of cellular proteins can lead to denaturation and targeting for proteasomal degradation [31]. However, oxidation of specific susceptible sites in proteins can also regulate function. Therefore, it is not clear to what extent ROS play a role in various aspects of cadmium-mediated cell proliferation, transformation, or death. Examining the evidence for the potential role of ROS in cadmium-induced cancer reveals the concentration dependence of cellular outcomes following cadmium exposure. Liu et al. [24] suggest that adaptive mechanisms in chronic low-dose exposure lead to lower ROS and apoptotic tolerance, thereby allowing proliferation of damaged cells with aberrant gene expression. On the other hand, higher levels of cadmium that produce increased expression of genes of oxidative stress in rat lung epithelia are associated with apoptotic death of more than half the cells [32]. It was also noted that aberrant oncogene expression seemed more important in transformation of rat hepatocytes by chronic cadmium exposure, with a minimal role suggested for ROS [33]. Thus, exposure to 1 ␮M cadmium for 28 weeks did not increase ROS levels, but gave rise to cells that produced aggressive tumours when injected into nude mice. Likewise, chronic 1 ␮M cadmium transformed human

urothelial cells and conveyed resistance to DNA damage, while higher concentrations killed the cells [34]. Nevertheless, oxidative DNA damage is important for cadmium-induced progression to neoplasia [11,24,35]. The role of ROS is probably more important in acute rather than chronic or environmental cadmium exposure. Electron spin resonance experiments with spin-trapping reagents have identified adducts from superoxide and peroxide in the bile of rats administered cadmium [24]. Using 13 C-labeled dimethysulfoxide, spin-trapped lipid radicals were also detected in bile of cadmium-overloaded rats [36]. Doubtless these ROS will activate ROS-sensitive transcription factors such as NF-␬B, AP-1, and Nrf2 [24]. It is clear that defective DNA repair is a contributing factor to cancer [37], and inhibition of DNA repair by cadmium is likely to play an important role in carcinogenesis [11,23]. Hengstler et al. [38] reported a correlation between single strand breaks in DNA of mononuclear leukocytes and air and blood cadmium levels in factory workers co-exposed to cadmium, cobalt and lead. Repair of 8-oxoguanine DNA damage in the lymphocytes of exposed workers was inversely correlated with strand breaks, and decreased with increasing cadmium exposure [38]. At noncytotoxic concentrations, cadmium inhibited base excision repair of DNA damaged by light in HeLa cells [39,40]. In nucleotide excision repair, cadmium inhibited the first step, which is recognition of DNA damage [41]. It has been shown that cadmium inhibits the binding to DNA of the xeroderma pigmentosum group A protein, XPA, a protein necessary for the recognition of DNA damage [42]. Cadmium also inhibits binding of the p53 tumour suppressor to DNA, and in MCF7 breast cancer cells cadmium suppresses the cell cycle arrest mediated by p53 in response to DNA damage [43]. Yeast exposed to low concentrations of cadmium showed decreased mismatch repair and increased hypermutability [44]. Furthermore, cadmium inhibits human 8-oxo-dGTPase, an enzyme that protects against the incorporation of 8-oxo-dGTP into DNA [45]. Thus, there is ample evidence that cadmium can inhibit DNA repair on multiple levels, leading to genome instability.

3. Cadmium and cell proliferation A recent detailed review has described effects of cadmium on signaling through Ca2+ , c-AMP, NO, NF-␬B, and developmental pathways such as Wnt signaling, in addition to kinases [29]. Here we will focus on well-established effects of cadmium on kinase activation, and down-stream events of immediate early response oncogene induction, as these events are likely involved in promotion and progression of cancer [46] and avoidance of cell death. Three major mitogen-activated protein kinases (MAPKs) exist in mammalian cells, namely Erk, Jnk, and p38 kinase [47]. In general, Erk is activated by growth factor receptors and stimulates cell proliferation, whereas Jnk and p38 are responsive to genotoxic agents and stresses [48–51]. Cadmium has been shown to activate each of these pathway [50,52,53], albeit with differential effects in different cell types. Cadmium (1.5 ␮M for up to 60 min) activated Erk1/2 and p38, but not Jnk, in chicken hepatoma cells [54]. Higher concentrations of cadmium (>100 ␮M for 3 h) persistently activated all three kinases in human lung carcinoma cells [50,55], whereas at lower concentrations Erk activity was decreased and Jnk was only transiently increased, with no effect on p38 [55]. Activation of p38 was confirmed at 100 ␮M cadmium in rat brain tumour cells, but was absent at 60 ␮M, whereas the opposite was true of Erk1/2 [52]. All three MAPK pathways are activated by cadmium in mesangial cells [56–58]. In general, in these experiments mesangial cells are put in a quiescent state by starvation in low-serum conditions

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for 48 h to minimize basal activity of kinases, prior to treatment with CdCl2 in serum-free conditions. Erk phosphorylation and kinase activity were significantly increased by 15 min treatment of rat mesangial cells with 0.1 ␮M cadmium and subsequently declined by 30 min [56]. With 10 ␮M CdCl2 , a second peak of activation occurred at 8 h. This biphasic pattern was also characteristic of Jnk activation. Suppression of Erk activation by PD98059 implicates MEK1/2 in cadmium-dependent Erk activation. Dominant negative transfections were used to show that Jnk activation in response to cadmium is mediated by MKK7 in preference to SEK1/MKK4 [57]. Activation of the third MAPK, p38, was observed following a 6 h treatment of mouse mesangial cells with 10 ␮M CdCl2 [58]. A low concentration of CdCl2 (0.5 ␮M) that activated Erk at 15 min in rat mesangial cells also increased phosphorylation of epidermal growth factor receptor (EGFR) at 5 min and activated the EGFRdependent PI3 kinase/Akt pathway at 15 min [59]. In addition to activating the MAPKs, cadmium is also found to activate Ca2+ /calmodulin-dependent protein kinase-II (CaMK-II) in mouse mesangial cells [58,60]. The CaMKs are a family of broadspecificity kinases that serve as general integrators of Ca2+ signaling [61,62]. They have been linked to oncogene induction in several cell lines [63,64]. The CaMK-II isoform is present in mesangial cells [65,66]. Treatment of mouse mesangial cells with 10 ␮M CdCl2 in serum-free medium caused a transient phosphorylation of CaMK-II on Thr286 at 60 s with a second peak occurring at 4 h [60]. Concentrations of 1 ␮M and above result in phosphorylation by 6 h [58]. Inhibitors of CaMK-II acting by different mechanisms, including KN93, KT5926, K252a , and autocamtide-2-related inhibitory peptide, all suppressed cadmium-dependent CaMK-II phosphorylation, indicating effects of cadmium on both Ca2+ -calmodulindependent phosphorylation and autophosphorylation of CaMK-II [60]. A general mechanism by which Cd2+ may increase the activity of multiple kinases is by increasing ROS, which in turn oxidize thiol groups on kinase-regulating phosphatases [67,68]. It also seems possible that Cd2+ inactivates multiple phosphatases by direct interaction with their thiol groups. One consequence of kinase activation is the induction of a number of immediate early response genes. These include oncogenes that serve as transcription factors capable of facilitating cell proliferation [23]. Interestingly, the effects of cadmium on oncogene expression are highly cell type-specific. Thus, it induces c-jun and c-myc, but not c-fos in myoblasts [69], whereas c-fos and egr-1 are induced in fibroblasts [70]. In normal rat kidney fibroblasts cadmium induces c-fos, c-jun, and c-myc [71]. It likewise induces c-fos, c-jun, and c-myc, as well as egr-1 in LLC-PK1 porcine proximal tubule cells [72]. In prostatic epithelial cells cadmium induces cjun and c-myc, but not c-fos [73], whereas c-fos, c-jun, and c-myc are all induced in BALB/c-3T3 cells [74]. Further, c-jun and c-myc are induced in chronically exposed liver epithelial cells [33] and in rat myoblasts [75]. Induction of c-jun, c-myc, and p53 by cadmium in prostatic epithelia precedes apoptosis [76]. Fos/Jun-dependent AP1 transcription factor activity is increased by 3 ␮M CdCl2 in mouse epidermal cells, and in mouse skin in vivo by topical application of CdCl2 [46]. One conclusion to draw from these observations is that cadmium quite consistently induces c-jun and c-myc, but shows variable effects on c-fos. In rat mesangial cells, however, it is clearly a transcriptional activator of c-fos [77].

4. Inhibition of apoptosis Cell death by apoptosis is one mechanism for eliminating unwanted (e.g., transformed) cells. Cadmium was found to suppress apoptosis induced by chromium in CHO cells [78]. Evidence has been presented that cadmium inhibits caspase-3 in this con-

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text [79]. However, the IC50 for caspase-3 inhibition by Cd2+ is ∼8.7 ␮M in intact CHO cells and significantly greater (∼31 ␮M) in a cell-free system [79]. Thus, even if caspase inhibition contributes to suppression of apoptosis by cadmium in intact cells, additional anti-apoptotic mechanisms must contribute. Transformation of cells by cadmium may itself be associated with a decrease in apoptotic potential. When human prostatic epithelia are transformed by cadmium, they show a decreased apoptotic potential that may in part result from decreased caspase expression, and an increase in the ratio of Bcl-2/Bax due to a decrease in pro-apoptotic Bax and an increase in anti-apoptotic Bcl-2 expression [15]. In this model, cadmium may select for cells defective in apoptosis [76]. After implicating oxidative stress in cadmium-induced apoptosis in lung epithelia [32], Hart et al. subsequently showed a decreased apoptotic response to oxidative stress in cadmium-adapted cells [80]. In non-transformed primary cultures of rat mesangial cells, treatment with 10 ␮M CdCl2 for 8 h in serum-free medium caused significant loss of cell viability without reproducible induction of apoptosis [81]. Therefore, to study the possible role of cadmium in mesangial cell apoptosis, we initiated apoptosis by independent means and looked for modulating effects of cadmium. We used treatment with camptothecin to produce DNA damage and activate the intrinsic, mitochondrial and caspase-9-dependent pathway, and exposure to TNF-␣ to activate the extrinsic, caspase8-dependent pathway. Definitions of apoptosis are considered in more detail below. With respect to camptothecin and TNF-␣ treatment, chromatin condensation and DNA laddering in the presence of cleavage of procaspase-3 to active caspase-3 were taken to indicate apoptosis. Caspase-8-dependent cleavage of the Bcl-2 family member, Bid, produces a truncated form of the protein, tBid, which also facilitates apoptosis by destabilizing mitochondria [82]. Caspase-8 activity and tBid were increased by TNF-␣ treatment of mesangial cells, and camptothecin increased caspase-9 activity. Cadmium (10 ␮M, 8 h) suppressed chromatin condensation, DNA laddering, and caspase-3 activation in response to both the extrinsic and intrinsic stimuli [81]. It also inhibited caspase-8 and -9 activities, decreased levels of tBid, and suppressed release of pro-apoptotic cytochrome c from mitochondria [81]. These results suggest that under some circumstances cadmium may act as a general inhibitor of caspase activation, but may also have other anti-apoptotic effects through factors affecting mitochondrial stability.

5. Cadmium and the kidney While cadmium has been reported to be linked to renal cancer [13,14,83,84], by far the more common effect of cadmium on the kidney is cell death, and contrasting its effects on the proximal tubular epithelium and the glomerular mesangium is an instructive framework for studying the pleiotropic effects of cadmium on cell death. The remainder of this review will focus on this comparison, drawing examples from other tissue and cell types when useful. The proximal tubule has long been recognized as a major target in cadmium-induced nephropathy [85], with proximal tubular necrosis and interstitial nephritis prominent features [86,87]. However, renal glomeruli are also exposed to circulating metals during plasma filtration, and may also be targets of cadmium [88–90]. The resident mesangial cell of the glomerulus is exposed directly to plasma and is not separated from the vascular lumen by a basement membrane. Rather, it elaborates the structural matrix of the mesangium, which itself participates in the filtration process. By virtue of their contractility, mesangial cells produce capillary deformation to regulate glomerular filtration [91,92]. In response to a variety of noxious stimuli, they acquire a proliferative, myofibrob-

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last phenotype in which they display characteristics of both smooth muscle cells and fibroblasts, for instance expressing ␣-smooth muscle actin and fibrillar collagen [93,94]. This is the phenotype that proliferates in culture, but cultured mesangial cells can be rendered quiescent by serum deprivation. Thus, in toxicity studies with cultured mesangial cells, there is an attempt to model events in the quiescent cell that may lead to either cell damage or activation. Cadmium toxicity has been studied in isolated glomeruli, cultured mesangial cells, and cultured podocytes [93–97]. Evidence of glomerular involvement in Cd nephrotoxicity comes from both animal experimentation and occupational health studies. Whereas intraperitoneal injection of Cd2+ into rats leads to reversible tubular proteinuria, chronic oral ingestion produces irreversible glomerular proteinuria [98]. Changes in glomerular morphology were noted in cadmium pigment workers [99]. Markers of glomerular vs. tubular injury implicate glomerular involvement in cadmium-exposed workers [100]. Occupational exposure to cadmium has been associated with an irreversible decrease in glomerular filtration rate [101,102]. Cadmium exposure can also cause an immune-mediated mesangial glomerulonephritis without tubular involvement [103]. A large prospective study conducted in industrially polluted regions of Belgium, the Cadmibel study mentioned above [16–18,100], found an association between cadmium body burden as assessed by 24 h urinary cadmium excretion, and excretion of ␤2 -microglobulin, retinol binding protein, N-acetyl-␤-d-glucosaminidase, and calcium. Significantly, evidence of glomerular involvement was also found. A later phase of the study also pointed out the adverse effects of co-exposures to other metals, notably lead and arsenic [104,105]. A study of citizens living in a cadmium-contaminated area also had markers of glomerular damage associated with higher cadmium excretion, and the effect was more marked in those who were exposed in childhood [106]. Cadmium is taken up by some cells through L-type-Ca2+ channels [107,108], although we were unable to demonstrate this in mesangial cells, where passive diffusion seems more important [109]. Uptake through anion transporters as the cadmium carbonate anion [110] is probably significant in cell culture systems with buffers based on CO2 , but less likely to be important in vivo. The divalent metal transporter, DMT-1, critical in iron metabloism, is also a potential source of cadmium uptake [111], but has not been explored in mesangial cells. It seems likely, then, that mesangial cell cadmium burden reflects exposure to exchangeable Cd2+ , either released from liver as a degraded metallothionein complex or largely bound to albumin [27]. The ZIP family of zinc transporters are also becoming recognized as of significance in reanl uptake of cadmium [112], but have not been explored in mesangial cells. An important study from the Karolinska Institute has identified a benchmark dose (defined as the lower 95% confidence limit on the dose that produces a definite response) for cadmium in a Swedish population with low environmental exposure [113,114]. Using urinary Cd2+ , tubular proteins, and glomerular filtration rate it is concluded that the benchmark doses for urinary cadmium are lower than critical concentrations previously reported, and the “critical dose level for glomerular effects was only slightly higher than that for tubular effects”. The authors note that whereas “the first sign of renal effects is tubular damage. . .more important, in succession to the tubular effects, cadmium may affect glomerular function.” The same authors have recently concluded there is no margin of safety between the onset of adverse effects and cadmium exposures in the general population [21]. Whereas the effects of cadmium on tubular epithelia are largely characterized by necrosis, the glomerular mesangial cell has proven to be useful model for studying other modes of cell death induced by cadmium in cell culture studies.

6. Cadmium-induced necrosis The above studies show that cadmium can act as a mitogen and increase cell proliferation in vivo, activate mitogenic kinases and proto-oncogene expression in vitro, and inhibit apoptosis under some circumstances. However, the principle effects of cadmium on the kidney are toxic and are marked by cell death. Necrosis is a mode of cell death that results from loss of integrity of the plasma membrane and breakdown of organelles with release of proteolytic enzymes that results in destruction of surrounding cells and initiation of an inflammatory response. It results from persistence of adverse events such as ROS-dependent peroxidation of membrane lipids, O2 deprivation and loss of ATP production leading to dysfunction of membrane ion pumps, and direct chemical attack by noxious substances. Thus, cadmium may initiate necrotic death through multiple mechanisms, such as ROS production and depletion of antioxidant defences (leading to lipid peroxidation and membrane damage), and enzyme inhibition (contributing to loss of ATP production and ionic regulation of the intracellular environment). Acute, but not chronic, parenteral cadmium exposure causes hemorrhagic necrosis in rat testes and the testes of non-human primates [5]. Acute oral administration causes necrosis of the gastric and intestinal mucosa [3]. In general, concentrations of greater than 50 ␮M cadmium cause necrosis both in vivo and in vitro, while low concentrations cause apoptosis [115]. As noted above, cadmium can induce proximal tubular necrosis in the kidney [86,87]. However, direct evidence of cadmiuminduced renal cell necrosis is not abundant. Both acute and chronic effects of cadmium on the kidney in animal studies, and chronic effects in humans, are characterized by cell loss and dysfunction with inflammation leading to interstitial nephritis and fibrosis, and proximal tubular degeneration with chronic proteinuria and tubular dysfunction characteristic of Fanconi syndrome [3,5,115]. In cultured mesangial cells, treatment with CdCl2 in the range of 0.1–20 ␮M for various periods of time and under various conditions leads to loss of viable cells almost exclusively by non-necrotic mechanisms [58–60].

7. Apoptotic-like cell death Apoptosis, sometimes referred to as programmed cell death (PCD), was discovered as a morphological variant of cell death several decades ago [116]. It is now variously defined on the basis of both morphological and biochemical features that include chromatin condensation, nuclear fragmentation, activation of caspases, and loss of mitochondrial membrane potential [117]. The program may unfold in several ways. Cell death may be caspase-dependent, and may evolve through both intrinsic (involving mitochondria, with or without DNA damage, and caspase-9 activation) and extrinsic (typically involving death receptor and caspase-8-mediated) pathways [118]. Alternatives include caspase-independent cell death mediated by apoptosis-inducing factor (AIF), endonuclease G (Endo G) released from mitochondria, or cathepsin released as the result of lyosomal membrane permeabilization [118]. Calpain activation may also interact with, or even substitute for, proteolytic activity of caspases against their targets [115,119]. Fuzziness in the nomenclature of apoptotic PCD reflects overlap and cross-talk in biochemical mechanisms. An expert panel on nomenclature has recently suggested that terms such as caspase-independent be avoided in qualifying subclasses of apoptosis [117], and specific biochemical indicators are preferred (e.g., annexin V-positive, Z-VAD-fmk-inhibitable, etc.). Nevertheless, the recent cadmium literature has distinguished apoptotic death from a second form that is variously described as

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late apoptosis or apoptotic-like, and so a further word on nomenclature is required. The term apoptotic-like PCD has been used to describe a form of PCD with a nuclear morphology characteristic of apoptosis. It is marked by compact chromatin condensation often with globular or crescent shapes (sometimes referred to as stage 2 chromatin condensation [120]). Apoptotic-like PCD has less compact chromatin condensation (stage 1 chromatin condensation) but also display markers of phagocytosis. It includes most forms of apoptosis where procaspase cleavage is not observed (caspase-independent apoptosis) [120–122]. Apoptotic-like PCD is mediated by noncaspase proteins including cathepsins, calpains and granzymes, and involves consequences of mitochondrial changes such as release and translocation of AIF and Endo G [120]. Other factors such as Smac/Diablo and the serine protease Omi/htra2 are responsible for removing caspase-inhibiting factors [122]. Thus, the descriptive term PCD alone is not widely used and more specifically caspase-independent cell death is often referred to in studies with cadmium. The terms apoptotic-like cell death and late apoptosis have also been used to describe a cultured cell population produced by cadmium exposure. Operationally, this is a population of cells that are identified by FACS as staining positively for both annexin V and propidium iodide. The idea is that cells initiated in the apoptotic program (thus displaying the phosphatidyl serine annexin V epitope) may eventually become compromised so as to lose integrity and stain with propidium iodide. However, the term late apoptosis seems to imply that cells progress from an early stage of annexin V positivity to later stain with propidium iodide. We have been unable to demonstrate any such temporal shift, and have evidence that the two populations (annexin V-positive with or without propidium iodide staining) arise independently and respond differentially to various interventions [59]. For instance, inhibition of CaMK-II and p38 kinase activation suppress apoptosis but not apoptotic-like death, while the antioxidant N-acetyl cysteine inhibits apoptotic-like death instead of apoptosis. Apoptotic-like cell death can occur through caspase-dependent or caspase-independent pathways [58]. Thus, we believe the term “late apoptosis” should be discouraged. Clearly cadmium promotes apoptosis through a caspasedependent apoptotic pathway (for a detailed review see [59]). It has been reported that cadmium can activate both caspase-8 and caspase-3 to induced apoptosis in human lymphoma U937 cells by the extrinsic pathway [123]. In the same study, cadmium also caused apoptosis through mitochondrial damage and caspase-9 and caspase-3 activation, i.e., the intrinsic pathway. Cadmium also activates caspase-8, caspase-8-dependent BH3interacting-domain death agonist (Bid) cleavage, initiates release of cytochorome c from mitochondria, and activates caspase-9 and caspase-3 in W38 lung epithelial fibroblasts [124]. Cells have been classified as type I and type II based on the level of procaspase8 expression and the involvement of Bid cleavage in mediating death through cross-talk to the intrinsic mitochondrial pathway [125,126]. By these criteria, mesangial cells [81] and W38 cells [124] are both type II cells. Cadmium induces caspase-independent death in cells through endonuclease activity such as AIF and Endo G, or other proteases such as Ca2+ -dependent cysteine proteases (calpain). Cadmium induces caspase-independent apoptosis through mitochondria and AIF translocation in MRC-5 fibroblasts [127]. We found that cadmium-induced caspase-independent apoptosis in mesangial cells associated with AIF nuclear translocation [58]. Furthermore, it has been shown that cadmium can induce caspase-independent apoptosis through calpain activation, and caspase-dependent apoptosis through caspase-3 in kidney proximal tubule cells [115,119]. Cross-talk between calpains and caspases is indicated;

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calpains may cleave and inactivate caspases, but may also partially cleave and activate caspase-3 [115]. 8. Kinases and apoptotic death Whereas Erk is generally accepted to be anti-apoptotic [128], the stress-activated kinases Jnk and p38 are thought to facilitate apoptosis in cells subjected to a variety of environmental stresses. However, a number of exceptions to these actions have been documented [51,81]. Erk activation is often biphasic, with an initial burst within minutes of stimulation followed by a second phase over a few hours [129]. Indeed, we observed this biphasic pattern with Erk, and also with Jnk, in cadmium-treated mesangial cells [56]. The sustained activation, possibly a consequence of increased ROS, has been considered responsible for cadmium-induced cell death [128], and caspase-dependent apoptosis initiated by low dose (1 ␮M) CdCl2 in HEK293 cells was decreased by inhibiting Erk activation [130]. On the other hand, blocking Erk activation decreased necrotic cell death in cadmium-treated murine macrophages [131]. Hao et al. [132] found that 0.5 ␮M cadmium was associated with increased cell proliferation and decreased Jnk phosphorylation in human embryonic kidney cells, whereas 50 ␮M cadmium lead to apoptosis and increased phosphorylation of Jnk and p38. Thus, the roles of kinase activation in cadmium-induced cell death depend on multiple factors, such as dose, time of exposure, and cell type, reflecting the multiple pathways involved the process. In mesangial cells, CdCl2 treatment at 10 ␮M or higher for up to 6 h in serum-free medium causes biphasic activation of CaMK-II and MAPKs [58,60]. Inhibition of either CaMK-II or p38, but not of Jnk or Erk, suppress cadmium-induced apoptosis by preventing translocation of AIF, independent of mitochondrial ␺ [58,60]. At lower concentrations, 0.5 ␮M CdCl2 for up to 24 h in serum-free conditions activates Erk, CaMK-II, and CaMK-II-dependent EGFR and PI3 kinase/Akt. However, 0.5 ␮M cadmium is not sufficient to produce a second activation of CaMK-II or Erk as is observed at higher concentrations, or to sustain activation of EGFR/PI3 kinase/AKT [59]. In these circumstances, inhibition of CaMK-II, EGFR, PI3/Akt and Erk all increase procaspase-3 cleavage. Annexin V and propidium iodide flow cytometry revealed that inhibition of CaMK-II increased apoptosis and apoptosis-like death in response to 0.5 ␮M cadmium [59]. 9. Autophagy Autophagy refers to the sequestration of cytoplasmic and organelle-derived material within double-membraned autophagosomes. While cells can display extensive autophagic vacuolization before or during death (termed cell death with autophagy), it is not clear whether this represents cell death by autophagy (autophagic cell death, ACD). The opinion has been expressed that autophagy is rarely if ever the mechanism by which cells actually die [133], and prevention of death by inhibition of autophagy should be demonstrated to conclude death is ACD. If inhibition of autophagy does not prevent cell death, then death is death with autophagy. Indeed, in most cases of knockout of essential autophagy (atg) genes death is not inhibited, although instances of overexpression being sufficient to kill cells are also known [117]. In general, it seems, autophagy is engaged for cell survival under stress through removal of damaged proteins and organelles. Human cord blood hematopoietic stem cells treated with 0.1 ␮M cadmium for 48 h showed evidence of mitochondrial damage, and at 10 ␮M cadmium cell loss was evident [134]. Morphological characteristics of apoptosis were absent, but autophagosomes/autophagolysosomes were prominent [134]. It is not clear whether this is an adaptive response or related to the

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Fig. 1. Multiple outcomes of exposure of mesangial cells to cadmium. High concentrations (e.g., 50 ␮M CdCl2 ) can cause necrosis. Intermediate concentrations (10 ␮M CdCl2 ) have been reported to induce autophagy, although whether this is a cause of death is unclear. The same concentration (10 ␮M) can inhibit caspase-dependent apoptosis initiated through either the extrinsic pathway by TNF-␣ or the intrinsic pathway by camptothecin (not shown). Exposure to 10 ␮M CdCl2 for 6 h can lead to caspase-independent apoptosis through both activation of CaMK-II and ROS-mediated activation of p38 kinase, and also to ROS-dependent apoptotic-like (annexin Vpositive/propidium iodide-positive) death. At low concentrations (0.5 ␮M CdCl2 ) short term (6 h) exposure initiates cell survival signals both through Erk and through CaMK-II-dependent activation of the PI3K/Akt pathway. However, prolonged exposure (24 h) to 0.5 ␮M CdCl2 initiates caspase-dependent apoptosis.

loss in cell number. Autophagy may act as a temporary survival pathway by removing the damaged mitochondria and keeping caspase activity under the threshold needed to trigger apoptosis [135]. In human umbilical vein endothelial cells, up to 10 ␮M cadmium inhibited TUNEL-positive apoptosis induced by deprivation of serum and basic fibroblast growth factor [136]. Autophagy was indicated by formation of acidic autophagolysosomal vacuoles and LC3-1 cleavage. However, the absence of experiments attempting inhibition of autophagy does not allow this study to distinguish whether ACD or death with autophagy is being observed. Wang et al. [137] reported that treatment of mesangial cells for 24 h in serum-replete medium caused both autophagy and apoptosis. At 12 ␮M CdCl2 , about 50% of the cells contained acidic vacuoles, but at 24 ␮M CdCl2 annexin V-positive apoptotic cells rose to 68%. Inhibition of autophagy with 3-methyladenine decreased cell death in 6 ␮M cadmium, suggesting it is ACD. In these experiments there is evidence that cadmium-induced ACD in mesangial cells is through multiple signals, including Ca2+ dependent activation of Erk [137], and ROS-dependent activation of glycogen synthase kinase-3␤ [138]. However, in view of the uncertainty surrounding ACD and death with autophagy, the role that autophagy may play in cadmium-induced cell death is still unclear. 10. Summary Cadmium exemplifies the two-sided nature of cell death and survival caused by an environmental hazard. Without any essential or beneficial biological effect, cadmium may on the one hand promote survival and proliferation of mutagenized cells, thereby acting as a carcinogen. On the other hand, it may enhance cell death by a variety of mechanisms, thus leading to tissue pathology and organ damage. In either case, the outcome for a cell exposed to cadmium is dependent not only upon the duration and level of exposure, but also on other factors intrinsic to the cell itself, and its current metabolic state. Some of the pathways leading to cell death and survival in mesangial cells are summarized in Fig. 1. The concentration dependence of the effects of cadmium are highlighted, and in the broadest terms, sub-micromolar concentrations lead to proliferation or delayed apoptosis, intermediate concentrations of 10 ␮M cause various types of apoptotic death, and only at very high concentration (>50 ␮M) can necrosis be expected. These results may generalize fairly well to many other cell types. Further studies at low concentrations are warranted to achieve further insight into cadmium as a carcinogen. Studies at intermediate concentrations

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