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Am J Physiol Renal Physiol (February 8, 2005). doi:10.1152/ajprenal.00401.2004
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Submitted on November 5, 2004
Accepted on February 3, 2005

p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice

Ganesan Ramesh1 and W. Brian Reeves1*

1 Division of Nephrology, Penn State College of Medicine, Hershey, PA, USA; Lebanon VA Medical Center, Lebanon, PA, USA

* To whom correspondence should be addressed. E-mail: wreeves{at}psu.edu.

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 (20mg/kg BW) developed severe renal dysfunction at 72hr (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 SKF86002 along with cisplatin showed less renal dysfunction (BUN: 55 ± 14 mg/dl, Creatinine: 0.3 ±0.02 mg/dl, p<0.05), less severe histologic 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 as compared with SKF86002 treated mice (P<0.05). Kidney mRNA levels of TNF-{alpha} were significantly increased in cisplatin treated mice when compared to either SKF86002 or saline treated animals. The hydroxyl radical scavenger DMTU (100mg/kg BW/day) 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}.




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