The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients.
Polymyxin B Nephrotoxicity: From Organ to Cell Damage
However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients. In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity.
Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects. Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity. Cisplatin cis-diamminedichloroplatinum II, CDDP is one of the most effective chemotherapeutic agents, widely used for the treatment of several malignant diseases including head and neck [ 1 , 2 ], esophageal [ 3 ], bladder [ 4 ], testicular [ 5 ], ovarian [ 6 ], uterine [ 7 ], cervical [ 8 ], breast [ 9 ], stomach [ 10 ], non-small [ 11 ], and small-cell lung cancers [ 12 ].
Therefore, CDDP-induced mucosal injury in gastrointestinal tract as well as myelosuppression due to the CDDP-caused injury of bone marrow, are severe and life-threatening side effects of CDDP-based therapy [ 14 , 15 , 16 , 17 ]. CDDP-induced nephrotoxicity is manifested as acute kidney injury AKI , salt or magnesium wasting and loss of urinary concentrating ability [ 18 , 19 , 20 , 21 , 22 ]. CDDP-caused renal dysfunction happens as a result of CDDP accumulation and biotransformation in the kidneys [ 18 , 19 , 20 , 21 , 22 ].
However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical application of safe and efficacious renoprotective drug, as an additive therapy for high dose CDDP-treated patients [ 24 ]. Until now, amifostine [ ethanethiol, 2-[ 3-aminopropyl amino] dihydrogen phosphate ester ] was the most commonly tested as nephroprotective agent against CDDP, but several serious side effects, including ototoxicity, hypotension, vertigo, hypocalciemia, severe nausea and vomiting, limited its clinical use [ 25 , 26 ].
Although some of the other thiol-generating cytoprotective agents sodium thiosulfate, reduced glutathione and diethyldithiocarbamate appeared to reduce CDDP-caused nephrotoxicity, all of them have demonstrated an unwanted tumor protecting effect which restricted their clinical use [ 27 , 28 ].
Consequently, there still remains an unmet need for the development of new, renoprotoctive agents in which activity should be relied on the modulation of pharmacokinetics and biological effects of CDDP in the kidneys. In this review paper, we emphasized current knowledge regarding molecular and cellular mechanisms involved in renal uptake, biotransformation and toxicity of CDDP in order to pave the way for new therapeutic approaches that can inhibit or minimize CDDP-dependent nephrotoxicity.
During glomerular filtration and tubular secretion, CDDP accumulates in the kidneys [ 20 ]. Renal proximal tubular epithelial cells PTECs absorb molecules from primary urine and are mainly exposed to urinary excreted xenobiotics [ 29 ]. Even non-toxic serum concentrations of CDDP may reach toxic levels in the kidneys, resulting in the development of renal dysfunction due to the severe injury of S3 segment of proximal tubules [ 30 , 31 ].
An important process mediating cellular accumulation of CDDP is transporter-mediated uptake of this drug. Findings obtained in several clinical trials demonstrated that magnesium replacement may down-regulate expression of OCT2 in PTECs resulting in attenuation of CDDP-induced nephrotoxicity [ 38 , 39 , 40 , 41 ]. Accordingly, magnesium supplementation 8—16 milliequivalents is now, along with short-duration and lower-volumn hydration, used for prevention of CDDP-caused renal injury [ 23 ].
Despite the fact that down-regulated Ctr1 expression in PTECs significantly decreased their apoptosis and necrosis in vitro [ 42 ], the effects of Ctr1 deletion or inhibition on the development of CDDP-induced AKI has not yet been examined in vivo. Accordingly, future experimental and clinical studies should be focused in exploring Ctr1 as a molecular target for the enhancement of cimetidine-induced attenuation of CDDP-caused-nephrotoxicity.
Additionally, it is important to highlight the fact that Ctr1 is localized on the basolateral side of both proximal and distal tubular epithelial cells.
The initial step of CDDP-induced nephrotoxicity is formation of glutathione conjugates in circulation, mediated by glutathione-S-transferase. After entering the kidney, glutathione-conjugates are cleaved to cysteinyl-glycine-conjugates by gamma glutamyl transpeptidase GGT , which is expressed on the surface of PTECs.
Aminopeptidase N APN converts cysteinyl-glycine-conjugates into cysteine-conjugates which are, after entering into the PTECs, further metabolized to highly reactive and nephrotoxic thiols by enzymic activity of cysteine-S-conjugate beta-lyase CCBL [ 22 , 44 ].
Nephrotoxic Mechanisms of Drugs and Environmental Toxins
Having in mind that, among all tissues, GGT has the highest activity in the kidneys, particularly on the apical surface of PTECs, this enzyme was considered as a potential target for the attenuation of CDDP-induced nephrotoxicity. Although findings obtained by Hanigan and colleagues strongly indicated an important role of GGT in toxification of CDDP, several other research groups showed opposite results suggesting that GGT could be considered as the main CDDP detoxification enzyme in the kidneys [ 47 , 48 ].
Daubeuf and colleagues and Paolicchi and coworkers demonstrated that GGT products cysteinyl-glycine-conjugates and the GGT substrate glutathione were able to covalently attach to CDDP rendering it non-toxic [ 47 , 48 ]. Indeed, GGT is, along with APN and CCBL, a member of multi-enzyme pathway which capacity to convert xenobiotic-glutathione conjugates to nephrotoxic metabolites is dependent on the synergistic activity of these three enzymes [ 49 ].
Similarly, due to their capacity to prevent the formation of a glutathione-cisplatin-conjugates, thiol agents have been tested as nephroprotective drugs in CDDP-treated patients. Nevertheless, renoprotective effects of Amifostine were not consistently observed in CDDP-treated patients and many severe side effects including dysfunction of vestibulocochlear, gastrointestinal and cardiovascular systems significantly limited its clinical use [ 25 , 26 ].
Accordingly, several recently conducted experimental and clinical trials focused their attention in the modulation of intracellular signaling pathways which were responsible for CDDP-induced cell cycle arrest or cell death. CDDP-induced nephrotoxicity is dose dependent and involves necrosis, apoptosis and necroptosis of renal cells [ 51 , 52 , 53 ]. In vitro studies revealed that necrotic cell death is caused by high levels of CDDP, while apoptosis is caused by lower concentrations of CDDP [ 51 , 52 ].
Inhibition of caspase-3 and caspase-9 suppressed CDDP-induced cell death [ 57 ], while cytochrome c release was diminished in CDDP-treated Bax-deficient mice [ 54 ], suggesting the important role of both extrinsic and intrinsic apoptotic pathways in the development of CDDP-induced AKI. In addition to necrosis and apoptosis, necroptosis is also observed in renal cells after CDDP treatment.
Deletion of genes involved in necroptotic pathway receptor-interacting protein 1 RIP1 and mixed lineage kinase domain-like protein MLKL managed to protect experimental animals against CDDP-induced AKI [ 61 , 62 ] indicating that pharmacological inhibitors of these molecules could be considered as possible therapeutic agents for the attenuation of CDDP-caused nephrotoxicity. Once the cisplatin enters PTECs, its complex interactions with the cellular environment convert it into a positively charged electrophile that has a high affinity to DNA [ 63 ]. This results in formation of intrastrand crosslink between two adjacent guanine residues within DNA [ 43 ].
More precisely, platinum atom of CDDP forms covalent bonds with N7 position of purine bases to form 1,2- or 1,3-intrastrand crosslinks and a lower percentage of interstrand crosslinks. CDDP-caused alterations in translation lead to the accumulation of misfolded proteins within ER, resulting in the development of ER stress. At the same time, positively charged CDDP electrophile preferentially accumulate in the negatively charged mitochondria affecting their function [ 66 ]. Thus, CDDP-induced prolonged ER stress and hypoxic injury provoke caspase-mediated apoptosis or induce extensive production of free radicals and reactive oxygen species ROS resulting in the development of oxidative stress [ 43 ].
P53 signaling pathways leading to tubular cell apoptosis after cisplatin treatment. Several lines of evidence confirmed that P53 protein was critically involved in the development of CDDP-induced nephrotoxicity [ 72 ]. CDDP treatment provokes increased expression and activation of p53 in injured kidneys where p53 regulates apoptosis of PTECs through transcriptional activation and repression of genes whose promoters contain pbinding sites Fig. Pharmacological inhibition as well as genetic deletion of p53 blocked the activation of both executioner caspases and protected PTECs from CDDP-caused apoptosis resulting in alleviation of CDDP-induced nephrotoxicity [ 74 ].
Although induction of pro-apoptotic molecules is dominant effect of p53 activation in CDDP-injured PTECs, p53 interferes with anti-apoptotic molecules p21 and TauT regulating their renoprotective function, as well. Pinduces down-regulated expression of TauT gene and, consequently, increases apoptosis in CDDP-injured renal cells [ 75 ].
Similarly, p53 may regulate activity of p21 protein, a well-known anti apoptotic regulator of cell survival [ 72 ]. Induction of p21 protein in renal cells is considered as an important renoprotective mechanism against CDDP-caused nephrotoxicity since both genetic deletion or pharmacological inhibition of p21 significantly augmented CDDP-provoked injury of PTECs [ 76 , 77 ].
And Drugs Toxins Nephrotoxic Of Environmental Mechanisms
Mechanistically, pmediated inhibition of cyclin-dependent kinase 2 CDK2 was mainly responsible for pdependent nephroprotection [ 78 ]. In addition to the regulation of apoptosis, p53 may contribute to the development of CDDP-caused nephrotoxicity by modulating autophagy which, as an adaptive mechanism, promotes PTECs survival during AKI [ 72 , 81 ].
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Based on all these findings, p53 represents potential molecular target for alleviation of CDDP-caused neprotoxicity. Experimental studies already demonstrated that temporary and reversible p53 suppression during cancer therapy can be relatively safe [ 88 ]. Additionally, selective, pharmacological inhibitors of p53 may be specifically delivered to renal cells without affecting primary tumor or metastatic lesions [ 89 , 90 ]. Furthermore, in some tumors p53 protein was responsible for tumor resistance to chemotherapeutics [ 81 ].
In these patients, systemic administration of p53 antagonists may result in nephroprotection and at the same time could sensitize malignant cells to anticancer drugs promoting their therapeutic efficacy [ 91 ]. Despite these promising expectations, it should be highlighted that due to the complex role that p53 has in regulation of cell survival, nephroprotection due to the selective p53 renal inhibition should be investigated, in detail, in CDDP-treated tumor-bearing animal models before it will be considered as one of possible therapeutic approaches for CDDP-treated patients.
Additionally, CDDP-induced extensive release of endogenous TLR-4 ligands may activate inflammasome complex in renal infiltrated immune cells resulting in enhanced production of inflammatory cytokines IL-1 and IL , further contributing to the development of renal inflammation [ ]. TLR-9 deficient mice had significantly reduced number of Tregs in injured kidneys and consequently developed enhanced immune response and inflammation in CDDP-injured kidneys [ ].
kessai-payment.com/hukusyuu/logiciels-espion/myfe-surveiller-un.php Development and progression of renal inflammation upon CDDP treatment is controlled and regulated by complex interaction between inflammatory and immunosuppressive cytokines produced either by CDDP-injured PTECs or renal-infiltrated immune cells Fig. Cell subtypes that play crucial role in the pathogenesis of cisplatin-induced AKI. Cisplatin-induced AKI involves the coordinated actions of proximal tubular epithelial, endothelial, innate and adaptive immune cells.
Faubel and coworkers revealed that caspase-1 activity was remarkably increased in the kidneys of CDDP-treated animals and that renal dysfunction was significantly reduced in caspase-1 deficient mice [ ]. CDDP treatment induces activation of inflammasome complex in renal infiltrated leukocytes, resulting in extensive ILA production.
In line with these observations, increased concentration of IL was noticed in sera and kidneys of CDDP-treated animals [ ]. Opposite to these findings are results recently obtained by Stremska and colleagues who demonstrated that two subpopulations of renal-infiltrated immunosuppressive and renoprotective cells Tregs and innate lymphoid cells, ILC expressed ST2 receptor and extensively proliferated in the presence of IL-2 and IL [ ].
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Several lines of evidence suggested that elevation in urine concentration of pro-inflammatory cytokines and chemokines may be considered as an important parameter for early diagnosis of CDDP-caused nephrotoxicity. Accordingly, measurement of urine levels of inflammatory mediators should be considered as an important approach for early diagnosis and prevention of CDDP-induced nephrotoxicity [ 22 ]. Among anti-inflammatory and immunosuppressive cytokines, it was well documented that IL, produced mainly by renal-infiltrated Tregs and tolerogenic dendritic cells, efficiently reduced CDDP-induced AKI and associated inflammation [ , , ].
DC-derived IL inhibits production of inflammatory cytokines in renal infiltrating T cells and macrophages [ , , , ]. In line with these findings, cell-based therapy based on autologous transplantation of IL producing Tregs and tolerogenic DCs in CDDP-injured kidneys should be further explored as potentially new therapeutic approach for renoprotection of CDDP-treated patients.
In addition to IL, IL-6 had been also considered as an important anti-inflammatory cytokine which may protect against CDDP-induced nephrotoxicity [ ]. An enhanced expression of IL-6 resulted in up-regulation of anti-oxidative enzymes in inflamed renal parenchyma which prevented the development of CDDP-caused renal dysfunction. In an analogy, genetic deletion of IL-6 significantly reduced activity of superoxide dismutase and increased expression of oxidative stress markers in CDDP-injured kidneys [ ].