Cisplatin-Induced Acute Renal Failure Is Associated with an Increase in the Cytokines Interleukin (IL)-1β, IL-18, IL-6, and Neutrophil Infiltration in the Kidney

Faubel, Sarah; Lewis, Eli C.; Reznikov, Leonid L.; Ljubanović, Danica Galešić; Hoke, Thomas S.; Somerset, Hilary; Oh, Dong-Jin; Lu, Lawrence; Klein, Christina L.; Dinarello, Charles A.; Edelstein, Charles L.

doi:10.1124/jpet.107.119792

Cited by 373 publications

(302 citation statements)

References 30 publications

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“…However, the synergetic cooperation Cyclosporine with TGFβ signaling pathway in the modulation of renal paracellular permeability has been confirmed by Feldman and colleagues [65]. In another study, expression of TGFβ has been demonstrated to be enhanced in cisplatin-induced Acute Kidney Injury (AKI) [66]. In agreement with these studies, we propose that that Cisplatin, Lead acetate and Cyclosporine can induce nephrotoxicity, at least in part, by affecting TGFβ signaling pathway, particularly Smad4 expression.…”

Section: Discussionsupporting

confidence: 74%

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Askari¹,

Abdullahi²,

Poortahmasebi³

et al. 2017

Biol syst Open Access

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It is well documented that use of Cisplatin, Lead acetate and Cyclosporine in the chemotherapy and medical interventions is highly associated with nephrotoxicity and interrelated comorbidities. Here, we proposed the possible molecular mechanisms responsible for nephrotoxicity of these compounds. We utilized the microarray dataset GSE59913 consisting of approximately 600 different compounds profiled in up to 8 different tissues. After analysis with GEO2R, gene expression profiles of three aforementioned compounds were integrated with protein-protein interactions (PPI) networks and topological properties of the networks were measured using Cytoscape software. We found several key genes and signaling pathways that seem to be involved in nephrotoxicity of the examined compounds. Myc and Smad4 were identified as principal players of three compounds' nephrotoxicity through various pathways. Our results revealed the critical functions of Il2, Jak-Stat, Mapk-Pi3k, TGFβ and Ca 2+ signaling pathways as well as novel biomarkers that may mediate the nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine. The significantly altered genes in the compound-treated samples were substantially correlated with regulation of cell proliferation, apoptosis, inflammatory responses and homeostatic processes. This study reveals the important hub genes, biological networks and key pathways as well as novel biomarkers involved in nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine.

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Section: Discussionsupporting

confidence: 74%

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Askari¹,

Abdullahi²,

Poortahmasebi³

et al. 2017

Biol syst Open Access

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“…In this model, a single injection of 30 mg/kg cisplatin induced AKI in C57BL/6 mice within 2-3 d (22,42,43). In our experiments, blood urea nitrogen was increased from the control level of 45 mg/mL to 194 mg/dL at d 3 of cisplatin treatment.…”

Section: Mir-34a Induction During Cisplatin Nephrotoxicity In Vivomentioning

confidence: 61%

“…In the in vivo model, 30 mg/kg cisplatin was used to induce kidney injury in C57/BL6 mice. This dose was also used by this and other laboratories in previous studies (22,42,43,45). It is noteworthy that cisplatin at 30 mg/kg induced apoptosis mainly in proximal and distal tubules in kidneys, and not in collecting tubules or glomeruli; some necrosis was induced and mainly localized in proximal tubules (42).…”

Section: Discussionmentioning

confidence: 99%

Untitled

Bhatt¹,

Mi²

2010

Mol. Med.

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MicroRNAs are small noncoding RNAs that are produced endogenously and have emerged as important regulators in pathophysiological conditions such as development and tumorigenesis. Very little is known about the regulation of microRNAs in renal diseases, including acute kidney injury (AKI). In this study, we examined the regulation of microRNA-34a (miR-34a) in experimental models of cisplatin-induced AKI and nephrotoxicity. By Northern blot and real-time polymerase chain reaction analyses, we detected an induction of miR-34a in vitro during cisplatin treatment of mouse proximal tubular cells and also in vivo during cisplatin nephrotoxicity in C57BL/6 mice. In cultured cells, miR-34a was induced within a few hours. In mice, miR-34a induction was detectable in renal tissues after 1 d of cisplatin treatment and increased to approximately four-fold of control at d 3. During cisplatin treatment, p53 was activated. Inhibition of p53 with pifithrin-α abrogated the induction of miR-34a during cisplatin treatment of proximal tubular cells. In vivo, miR-34a induction by cisplatin was abrogated in p53-deficient mice, a result that further confirms a role for p53 in miR-34a induction during cisplatin nephrotoxicity. Functionally, antagonism of miR-34a with specific antisense oligonucleotides increased cell death during cisplatin treatment. Collectively, the results suggest that miR-34a is induced via p53 during cisplatin nephrotoxicity and may play a cytoprotective role for cell survival.

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“…80 However, not all studies document a consistent blockade of intrarenal inflammation and tubular necrosis in postischemic or toxic AKI in models upon blockade of the IL-1 axis. [81][82][83] These findings may imply that IL-1 is not a universal mediator of AKI and its role is context-dependent. Models of acute glomerular injury pose new questions.…”

Section: Aki Modelsmentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

209

152

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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Cisplatin-Induced Acute Renal Failure Is Associated with an Increase in the Cytokines Interleukin (IL)-1β, IL-18, IL-6, and Neutrophil Infiltration in the Kidney

Abstract: We have demonstrated that caspase-1-deficient (caspase-1

Cited by 373 publications

References 30 publications

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

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Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

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