Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity

Volarević, Vladislav; Djokovic, Bojana; Gazdic, Marina; Harrell, Carl Randall; Fellabaum, Crissy; Djonov, Valentin; Arsenijević, Nebojša

doi:10.1186/s12929-019-0518-9

Cited by 270 publications

(185 citation statements)

References 142 publications

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“…Yet, application of holo-Lcn2 led to recovery of F-actin fiber distribution across the cells and, thus, cellular integrity. In order to sustain these findings, we analyzed PCNA and stathmin as accepted regenerative markers in kidney injury [22,42,43]. Furthermore, the expression of both stathmin and PCNA mRNA is known to decrease following Cisplatin application in vivo [34], which is in line with our results in vitro.…”

Section: Discussionsupporting

confidence: 76%

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

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Thiemens

Mertens

et al. 2020

IJMS

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Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5 µM Cisplatin for 24 h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2−/− mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored.

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Section: Discussionsupporting

confidence: 76%

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

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Thiemens

Mertens

et al. 2020

IJMS

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“…The endoplasmic reticulum (er) can serve a critical role in cP cellular toxicity (13,14). The er is the organelle responsible for synthesis and maturation of proteins, calcium storage and maintenance of cell homeostasis (15). cellular events, such as oxidative stress, can trigger er stress (erS).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

Chai

Zhu

et al. 2020

Mol Med Report

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cisplatin (cP) is an effective antineoplastic agent; however, cP-induced acute kidney injury (aKi) seriously affects the prognosis of patients with cancer. endoplasmic reticulum (er) stress (erS)-induced apoptosis serves a pivotal role in the pathogenesis of cP-induced aKi. dexmedetomidine (dex), a potent α 2 adrenergic agonist, has been reported to exert protective effects against aKi. However, the protective effects of dex against cP-induced aKi and the potential molecular mechanisms remain unknown. in the present study, male Sprague-dawley rats were divided into four groups (n=10/group), as follows: control group; cP group, rats received an intraperitoneal (i.p.) injection of 5 mg/kg cP; dex + cP group, rats received an i.p. injection of 25 µg/kg dex immediately after cP treatment; and dex + cP + atipamezole (atip) group, rats received an i.p. injection of 250 µg/kg atip, an α 2 adrenoreceptor (α 2 ar) antagonist, and then received the same treatment as the dex + cP group. rats were anesthetized and sacrificed 96 h after CP injection. Subsequently, serum blood urea nitrogen (Bun) and serum creatinine (Scr) were analyzed, and kidney samples were collected for analyses. Pathological changes were examined using hematoxylin and eosin staining, and protein expression levels were assessed using western blotting and immunohistochemical staining. in addition, apoptosis was examined using a terminal deoxynucleotidyl transferase duTP nick-end labeling assay. The present results suggested that dex protected against cP-induced aKi by attenuating histological changes in the kidney, serum Bun and Scr production. Furthermore, the expression levels of 78-kda glucose-regulated protein, c/eBP homologous protein and caspase-12, and the apoptotic rate in the kidney were decreased following dex treatment. in addition, the expression levels of phosphorylated (p)-Pi3K and p-aKT in the dex + cP group were significantly increased. Conversely, the renoprotective effects of dex were attenuated following the addition of atip. in conclusion, dex may alleviate cP-induced aKi by attenuating erS-induced apoptosis, at least in part, via the α 2 ar/Pi3K/aKT signaling pathway.

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“…Moreover, the therapeutic effects of polysulfide and H 2 S on cisplatin-induced inflammation response were also assessed in mice as inflammation is critically involved in the pathologies of cisplatin nephrotoxicity [ 27 ]. As previously described [ 28 , 29 ], the levels of TNF-α and IL-1β in both serum and renal tissues were significantly enhanced in cisplatin-induced mice, and these upregulated pro-inflammatory cytokines were diminished by Na 2 S 4 , NaHS, and GYY4137 ( Figure 5 A–B).…”

Section: Resultsmentioning

confidence: 99%

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

Sun

Leng

et al. 2020

IJMS

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Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase β (IKKβ), followed by decreased phosphorylation of STAT3 and IKKβ. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKβ and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.

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Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity

Cited by 270 publications

References 142 publications

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

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