Cilostazol Renoprotective Effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 Underlies Its Novel Effect in a Model of Ischemia-Reperfusion

Abstract

Cilostazol, a phosphodiesterase-III inhibitor, reportedly exhibits positive effects against ischemia/reperfusion (I/R)-induced injury in several models. However, its potential role against the renal I/R insult has not been elucidated. To test whether the PPAR-γ (of peroxisome proliferator activated receptor gamma) pathway is involved in the cilostazol effect, rats were randomized into sham, I/R, cilostazol (50 and 100 mg/kg per day, orally), pioglitazone (3 and 10 mg/kg per day, orally) and their combination at the low dose levels. Drugs regimens were administered for 14 days prior to the I/R induction. Pretreatment with cilostazol or pioglitazone provided significant protection against the I/R-induced renal injury as manifested by the attenuated serum levels of creatinine, blood urea nitrogen and cystatin C. Both drugs have also opposed the I/R-induced elevation in tissue contents/activity of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Κim-1), nuclear factor-κB, interleuκin-18, caspase-1, as well as malondialdehyde, iNOS, myeloperoxidase, ICAM-1 and VCAM-1. Nevertheless, the drugs increased both the PPAR-γ transcriptional activity and the content of glutathione. Furthermore, combining the two low doses of both drugs produced effects comparable to that of the high dose level of either drug, advocating the fortification of pioglitazone renoprotective effect when given concomitantly with cilostazol. In conclusion, cilostazol purveyed conceivable novel renoprotective mechanisms and alleviated incidents associated with acute renal injury either alone or in combination with pioglitazone partially via the elevation of PPAR-γ besides the amendment of the aforementioned biomarkers.

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

“…This was evidenced by increased renal MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory signals; findings which are consistent with previous literature [41]. Evidence indicates that the activation of monocytes and macrophages is linked to the release of an array of proinflammatory cytokines which trigger and perpetuate the inflammatory response in diverse renal pathologies [6].…”

“…Renal Kim-1 is upregulated in proximal tubular injury whereas increased NGAL confirms the damage to renal nephrons [38]. These events can be regarded as compensatory mechanisms against renal damage since Kim-1 serves to suppress apoptosis and aids in tubular re-epithelization while NGAL behaves as an adhesion molecule that abrogates epithelial shedding [41]. Interestingly, current findings demonstrated that CM exerted renoprotective actions as confirmed by leveling-off these injury biomarkers; events that are in agreement with the reported CM attenuation of cisplatin- [21], Diabetes mellitus- [19] and gentamicin-induced nephrotoxicities [20].…”

Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction

“…[41][42][43][44] Several lines of studies reported that GM-induced GSH level depletion might be due to excess generation of free radicals or increased consumption in the protection of -SH group-containing proteins and decreased SOD antioxidant enzymes associated with overproduction of superoxide anions and hydrogen peroxide. 18,[45][46][47] In consistent with the previous finding, our results showed that GM administration increased MDA level as an end product of lipid peroxidation while decreased GSH and SOD levels in renal tissue.…”

Tanshinone IIA pretreatment attenuates ischemia/reperfusion-induced renal injury

“…MPO activity was significantly increased in the ischemic brain tissue of rats at 24 h after I/RIRI, which indicates that I/RIRI is inflammatory reaction participated by neutrophile granulocyte (23). Previous studies reported that after reduction of I/RIRI, the expression level of intercellular adhesion molecule 1 (ICAM-1) or reduction of neutrophile granulocyte which can reduce I/RIRI and protective effect to renal (24). In present study, it was found that tanshinone IIA significantly reduced the I/RIRI-induced MPO activity in I/RIRI rats.…”