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Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

ABSTRACT: Background:Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. Methods:Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. Results:Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-?B and CD68-positive cell concentrations. Conclusions:Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.

SUBMITTER: Humanes B

PROVIDER: S-EPMC6251639 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

Humanes Blanca B Camaño Sonia S Lara Jose Manuel JM Sabbisetti Venkatta V González-Nicolás María Ángeles MÁ Bonventre Joseph V JV Tejedor Alberto A Lázaro Alberto A

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20171001 10

<h4>Background</h4>Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use ...[more]

PMID: 28340076

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Project description: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.

Project description:Lipopolysaccharide (LPS), a gut-transmitted endotoxin from Gram-negative bacteria, causes inflammatory diseases leading to the loss of gut barrier integrity and has been identified as a major pathogenic stimulator in many dysfunctions. Hence, supplementation with probiotics is believed to be one of the most effective strategies for treating many inflammatory gut disorders. Although probiotics are known to have a variety of therapeutic characteristics and to play a beneficial role in host defense responses, the molecular mechanisms by which they achieve these beneficial effects are unknown due to species- and strain-specific behaviors. Therefore, in this study, the protective role of five indigenous lactic acid bacterial strains in ameliorating LPS-induced gut barrier impairment in the C57BL/6 mice model was elucidated. Lacticaseibacillus rhamnosus LAB3, Levilactobacillus brevis LAB20, and Lactiplantibacillus plantarum LAB31 were isolated from infant feces; Pediococcus acidilactici LAB8 from fermented food (Bekang); and Lactiplantibacillus plantarum LAB39 from beetroot. Intraperitoneal injection of LPS (10 mg/kg of body weight) increased the levels of lipocalin and serum markers TNF-α, IL-6, and IL-1β, and the overall disease activity index in the treated group. Furthermore, gene expression of NF-kB, IL-12, and Cox-2; mucin-producing genes Muc-2 and Muc-4; and intestinal alkaline phosphatase (IAP) was deleteriously altered in the ileum of LPS-treated mice. Furthermore, LPS also induced dysbiosis in gut microbiota where higher abundances of Klebsiella, Enterobacter, and Salmonella and decreased abundances of Lactobacillus, Bifidobacteria, Roseburia, and Akkermansia were observed. Western blotting results also suggested that LPS treatment causes the loss of gut barrier integrity relative to the pre-supplementation with LAB strains, which enhanced the expression of tight junction proteins and ameliorated the LPS-induced changes and inflammation. Taken together, the study suggested that LAB3 and LAB39 were more potent in ameliorating LPS-induced gut inflammation and dysbiosis.

Project description:Key Points Long-term effects of cisplatin are understudied. This study is the first to examine the role of macrophages in cisplatin-induced fibrosis. Depletion of kidney-resident macrophages ameliorated cisplatin-induced fibrosis, whereas depletion of infiltrating macrophages had no effect. This study highlights a pathogenic role for kidney-resident M2 macrophages in the development of fibrosis with repeated nephrotoxic injury. Visual Abstract Background Cisplatin-induced kidney injury remains a major obstacle in utilizing cisplatin as a chemotherapeutic for solid-organ cancers. Thirty percent of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long-term declines in kidney function and development of chronic kidney disease (CKD). Modeling cisplatin-induced kidney injury in mice has revealed that repeated low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. Macrophages play a role in some of these processes, including immune response, wound healing, and tissue remodeling. Depleting macrophage populations in the kidney reduced fibrosis development in other models of renal fibrosis. Methods We used either C57BL/6 mice with a Ccr2 genetic knockout or liposome encapsulated clodronate (Clodrosome) to deplete macrophage populations during repeated 9 mg/kg cisplatin treatments. We assessed how immune cell populations were altered in the blood and kidney of these mice and how these alterations affected development of renal fibrosis and kidney injury. Results We found that Clodrosome treatment decreased collagen deposition, myofibroblast accumulation, and inflammatory cytokine production, whereas Ccr2 genetic knockout had no effect on these markers after cisplatin treatment. Additionally, Ccr2−/− mice had decreased levels of F4/80lo infiltrating macrophages in the kidney after cisplatin treatments, but Clodrosome treatment depleted F4/80hi resident and CD206+ M2 macrophages. Conclusions These data suggest that Clodrosome depletion of F4/80hi and M2 macrophages in the kidney attenuates development of renal fibrosis after repeated low doses of cisplatin.

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Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

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Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

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