title: p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice.
abstract: Cisplatin is an important chemotherapeutic agent but can cause acute renal injury. Part of this acute renal injury is mediated through tumor necrosis factor-alpha (TNF-alpha). The pathway through which cisplatin mediates the production of TNF-alpha and injury is not known. Cisplatin activates p38 MAPK and induces apoptosis in cancer cells. p38 MAPK activation leads to increased production of TNF-alpha in ischemic injury and in macrophages. However, little is known concerning the role of p38 MAPK in cisplatin-induced renal injury. Therefore, we examined the effect of cisplatin on p38 MAPK activity and the role of p38 MAPK in mediating cisplatin-induced TNF-alpha production and renal injury. In vitro, cisplatin caused a dose-dependent activation of p38 MAPK in proximal tubule cells. Inhibition of p38 MAPK activation led to inhibition of TNF-alpha production. In vivo, mice treated with a single dose of cisplatin (20 mg/kg body wt) developed severe renal dysfunction at 72 h [blood urea nitrogen (BUN): 154 +/- 34 mg/dl, creatinine: 1.4 +/- 0.4 mg/dl], which was accompanied by an increase in kidney p38 MAPK activity and an increase in infiltrating leukocytes. However, animals treated with the p38 MAPK inhibitor SKF-86002 along with cisplatin showed less renal dysfunction (BUN: 55 +/- 14 mg/dl, creatinine: 0.3 +/- 0.02 mg/dl, P < 0.05), less severe histological damage, and fewer leukocytes compared with cisplatin+vehicle-treated animals. Serum levels of TNF-alpha, sTNFRI, and sTNFRII also increased significantly in cisplatin-treated mice compared with SKF-86002-treated mice (P < 0.05). Kidney mRNA levels of TNF-alpha were significantly increased in cisplatin-treated mice compared with either SKF-86002- or saline-treated animals. The hydroxyl radical scavenger DMTU (100 mg.kg body wt(-1).day(-1)) prevented the activation of p38 MAPK by cisplatin both in vitro and in vivo. DMTU also completely prevented cisplatin-induced renal injury (BUN: 140 +/- 27 vs. 22 +/- 2 mg/dl, P < 0.005) and the increase in serum TNF-alpha (33 +/- 7 vs. 4 +/- 2 pg/ml, P < 0.005) and kidney TNF-alpha mRNA in vivo. We conclude that hydroxyl radicals, either directly or indirectly, activate p38 MAPK and that p38 MAPK plays an important role in mediating cisplatin-induced acute renal injury and inflammation, perhaps through production of TNF-alpha.
authors.affiliation: Division of Nephrology, Pennsylvania State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramesh
authors.forename: W Brian
authors.initials: WB
authors.lastname: Reeves
mesh_terms: D000818:Animals; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C038983:1,3-dimethylthiourea; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D048051:p38 Mitogen-Activated Protein Kinases; D013890:Thiourea; C093642:SB 203580; D002945:Cisplatin