Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection

Humanes, Blanca; Camaño, Sonia; Lara, J M Tunon de; Sabbisetti, Venkatta; González-Nicolás, María Ángeles; Bonventre, Joseph V.; Tejedor, Alberto; Lázaro, Alberto

doi:10.1093/ndt/gfx005

Cited by 63 publications

(68 citation statements)

References 60 publications

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“…Therefore, cilastatin, which fully restores both PI (38:4) and LPI(18:0) and tends to restore other PI species too, is able to block cisplatininduced apoptosis and its downstream effects. These results show, for the first time, the underlying process of our previous observations (10,12,15). Moreover, other phospholipids, such as PC, can also be a source of AA via PLA2.…”

Section: Discussionsupporting

confidence: 75%

“…2 and 4). Cisplatin activates nuclear factor kappa  [thus triggering an increase in proinflammatory molecules and interleukins (15)], which can induce PLA2 (59). In addition, cisplatin is able to increase production of inflammatory species (15) during renal damage.…”

Section: Discussionmentioning

confidence: 99%

“…Cilastatin, a selective inhibitor of renal dehydropeptidase-I (DHP-I), has been shown to act as an effective nephroprotector for cisplatin in in vitro (12) and in vivo (9, 10) models without affecting the antitumor effect of the drug. Its ability to inhibit apoptosis and OS and to decrease inflammatory response in renal proximal tubule epithelial cells (RPTECs) has been demonstrated (10,(12)(13)(14)(15), although the complete mechanism of nephroprotection of cilastatin is not completely understood.…”

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confidence: 99%

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Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity

Moreno-Gordaliza

Esteban-Fernández

Lázaro

et al. 2018

Journal of Lipid Research

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Nephrotoxicity is a major limitation to cisplatin antitumor therapies. Cilastatin, an inhibitor of renal dehydropeptidase-I, was recently proposed as a promising nephroprotector against cisplatin toxicity, preventing apoptotic cell death. In this work, cilastatin nephroprotection was further investigated in a rat model, with a focus on its effect on 76 renal lipids altered by cisplatin, including 13 new cisplatin-altered mitochondrial cardiolipin species. Lipid imaging was performed with MALDI mass spectrometry imaging (MALDI-MSI) in kidney sections from treated rats. Cilastatin was proved to significantly diminish the lipid distribution alterations caused by cisplatin, lipid levels being almost completely recovered to those of control samples. The extent of recovery of cisplatin-altered lipids by cilastatin turned out to be relevant for discriminating direct or secondary lipid alterations driven by cisplatin. Lipid peroxidation induced by cisplatin was also shown to be reduced when cilastatin was administered. Importantly, significant groups separation was achieved during multivariate analysis of cortex and outer-medullary lipids, indicating that damaged kidney can be discerned from the nephroprotected and healthy groups and classified according to lipid distribution. Therefore, we propose MALDI-MSI as a powerful potential tool offering multimolecule detection possibilities to visualize and evaluate nephrotoxicity and nephroprotection based on lipid analysis.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity

Moreno-Gordaliza

Esteban-Fernández

Lázaro

et al. 2018

Journal of Lipid Research

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“…These findings demonstrated that cilastatin also protected against the nephrotoxicity of diclofenac. In a previous study, cisplatin induced oxidative stress, inflammation and apoptosis, which could be inhibited by the co‐administration of cilastatin (Humanes et al, ; Humanes et al, ). In the present study, diclofenac also induced elevated levels of oxidation products, cytokine production and apoptosis in the kidney (Figures b and a), which was consistent with the results of a previous study (Fattori et al, ) and could be prevented by cilastatin treatment.…”

Section: Discussionmentioning

confidence: 92%

Protective effect of cilastatin against diclofenac‐induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters

Huo

Meng

Wang

et al. 2020

British J Pharmacology

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Background and Purpose: Diclofenac is a widely used nonsteroidal antiinflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac. Experimental Approach: The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac. Key Results: Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OATdependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs. Conclusion and Implications: Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.

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“…The mechanism of anticancer impact of cisplatin is an interaction with purine base DNA function, which leads to stopping the proliferation of tumor cells and inducing apoptosis (8). Free oxidant radicals reduce glomerular filtration and cause acute nephrotoxicity in the tubules, particularly S3 segment of proximal tubules (9) The complications of cisplatin Cisplatin has numerous side effects, one of them is nephrotoxicity by inflammation in the interstitial tissue (10). Hypomagnesemia is another complication which is due to loss of magnesium through the urine because of damage to the thick, ascending part of Henle loop and distal tubules.…”

Section: Mechanisms Of Cisplatin Actionmentioning

confidence: 99%

Mechanistic impact of medicinal plants affecting cisplatin-induced nephrotoxicity; an overview

Hooshyar¹,

Sedighi²,

Hooshmand³

et al. 2019

Immunopathol Persa

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Cisplatin is a powerful chemotherapy drug that is administered to treat a wide range of cancers. However, its clinical use is limited due to kidney damage and the reduction in glomerular filtration rate that occurs in 15% to 30% of patients. Several mechanisms lead to renal dysfunction after cisplatin administration, including direct damage to proximal tubular epithelial cells that causes necrosis and apoptosis. Cisplatin administration is accompanied by the production of reactive oxygen species (ROS), which causes lipid peroxidation, proteins and nucleic acids oxidation, cell membrane degradation, and finally reduction in glomerular filtration. The most prominent effect of cisplatin-induced nephrotoxicity (CIN), which can be progressive, is hypomagnesemia, Fanconi syndrome and anemia. Cisplatin nephrotoxicity is more prominent in individuals who received higher doses of this drug, or in patients who had previous chemotherapy regimen and presence of renal dysfunction. This paper is sought to describe cisplatin nephrotoxicity and the protective role of medicinal plants in preventing the renal toxicity. In this regard, the role of antioxidants will be specifically addressed.

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Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection

Cited by 63 publications

References 60 publications

Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity

Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity

Protective effect of cilastatin against diclofenac‐induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters

Mechanistic impact of medicinal plants affecting cisplatin-induced nephrotoxicity; an overview

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