Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

Abstract

Recently, we demonstrated that peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPARalpha ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-alpha, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARalpha ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARalpha ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARalpha null mice. In addition, we observed that cisplatin-induced NF-kappaB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARalpha ligand. These results demonstrate that PPARalpha exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-kappaB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.

Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase

“…Both the Jun Nterminal kinase (Francescato et al 2007) and peroxisome proliferator-activated receptor (Li et al 2005;Lee et al 2006) pathways have been shown to mediate the production of inflammatory cytokines; interestingly, inhibition of these pathways is protective against cisplatin-induced nephrotoxicity (Lee et al 2006;Francescato et al 2007). We hypothesize that the anti-inflammatory effects of sEH inhibition are responsible for the protection against cisplatin-induced nephrotoxicity.…”

Cisplatin up‐regulates ICAM‐1 expression in endothelial cell via a NF‐κB dependent pathway

“…However, the currently available data are somewhat conflicting as to the precise role of cisplatin in regulating NF-κB activation and DNA binding. (24,25,34,36,37) Our data also suggested that the response of NF-κB to distinct cancer therapies might also vary, depending on the cell type and context, since numerous evidences showed that NF-κB act as a antiapoptotic factor and tumor promotor, while under some circumstances NF-kB can contribute to genotoxic stress-induced apoptosis. (38) Intercellular adhesion molecule-1 (ICAM-1, CD54) is a member of the immunoglobulin superfamily.…”

“…Approaches to reduce the incidence and severity of cisplatin-associated toxicity are under intensive investigation indicate that. (9,12,18,24) Cisplatininduced nephrotoxicity, ototoxicity, and neurotoxicity have been associated with potential microvascular damage, (17)(18)(19) and previous animal experiments and clinical reports have demonstrated that vascular factors (20)(21)(22) contribute to renal dysfunction following exposure to cisplatin. The mechanisms underlying these troublesome vascular-injury-associated side-effects, which are regarded as crucial in the pathogenesis of tissue damage, might involve the proliferation inhibition effect of cisplatin on endothelial cells in vitro (18,32,33) and in vivo.…”

“…This releases NF-κB and allows it to translocate freely to the nucleus, where it regulates the expression of target genes. (28) The finding that cisplatin induces ICAM-1 expression, (24) and the fact that NF-κB is the most important inducible transcription factors in the ICAM-1 promoter, (29) led us to determine the functionality of the NF-κB signaling in cisplatin exposure HUVECs. Treatment of HUVECs with 6 µg/mL (this concentration arose significantly up-regulated level of ICAM-1 in HUVECs as indicated above) cisplatin produced a rapid reduction in the IκBα protein (Fig.…”

Peroxisome proliferator-activated receptors: Targets for the treatment of metabolic illnesses (Review)

“…They are also incapable of responding to fasting states, resulting in hypoacetonemia, which is associated with severe hypothermia and hypoglycemia (7). PPARα is associated with the inflammatory process as knockout mice show a prolonged inflammatory response (9)(10)(11). Furthermore, these mice present alterations in their cardiac function (12).…”