title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, October Six University, Giza, Egypt.
authors.forename: Diaa
authors.initials: D
authors.lastname: Ragab
authors.affiliation: Department of Pharmacology and Toxicology, Cairo University, Cairo, Egypt.
authors.forename: Dalaal M
authors.initials: DM
authors.lastname: Abdallah
authors.affiliation: Department of Pharmacology and Toxicology, Cairo University, Cairo, Egypt.
authors.forename: Hanan S
authors.initials: HS
authors.lastname: El-Abhar
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D020170:Caspase 1 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D000077407:Cilostazol; D003404:Creatinine / Q000097:blood; D055316:Cystatin C / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D000077205:Pioglitazone; D020011:Protective Agents / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D020170:Caspase 1; D015815:Cell Adhesion Molecules; D000077407:Cilostazol; D003404:Creatinine; D055316:Cystatin C; D007004:Hypoglycemic Agents; D018799:Intercellular Adhesion Molecule-1; D020382:Interleukin-18; D000071068:Lipocalin-2; D054834:Lipocalins; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma; D009195:Peroxidase; D058987:Phosphodiesterase 3 Inhibitors; D000077205:Pioglitazone; D020011:Protective Agents; D011518:Proto-Oncogene Proteins; D013777:Tetrazoles; D045162:Thiazolidinediones; D019010:Vascular Cell Adhesion Molecule-1; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat