TY - JOUR T1 - The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 518 LP - 525 DO - 10.1124/jpet.114.213769 VL - 349 IS - 3 AU - Hyun-Jung Kim AU - Kameswaran Ravichandran AU - Abdullah Ozkok AU - Qian Wang AU - Zhibin He AU - Alkesh Jani AU - Danica Ljubanovic AU - Ivor S. Douglas AU - Charles L. Edelstein Y1 - 2014/06/01 UR - http://jpet.aspetjournals.org/content/349/3/518.abstract N2 - Triptolide, a traditional Chinese medicine, has anti-inflammatory, antiproliferative, and proapoptotic properties. As interstitial inflammation and tubular apoptosis are features of cisplatin-induced acute kidney injury (AKI), we determined the effect of the water-soluble triptolide derivative 14-succinyl triptolide sodium salt (PG490-88) in a mouse model of cisplatin-induced AKI. PG490-88 resulted in a significant decrease in blood urea nitrogen (BUN), serum creatinine, and acute tubular necrosis (ATN) score, and a nonsignificant increase in tubular apoptosis score in AKI. The mitogen-activated protein kinase (MAPK) pathway is activated in AKI. On immunoblot analysis, phosphoextracellular signal-regulated kinase (p-ERK) was increased 3.6-fold in AKI and 2.0-fold inhibited by PG490-88. Phospho-c-Jun N-terminal kinase (p-JNK) was increased in AKI. PG490-88 resulted in a nonsignificant decrease in p-JNK. Phospho-p38 was not affected by cisplatin or PG490-88. MAPK phosphatase-1 (MKP-1) that negatively regulates MAPK signaling has not previously been studied in AKI. MKP-1 activity was not affected by cisplatin or PG490-88. Changes in p-ERK, p-JNK, and MKP-1 were confirmed on reverse protein phase analysis. The ERK inhibitor U0126 resulted in lower BUN and serum creatinine, suggesting a mechanistic role of ERK in AKI. The increase in interleukin-1α (IL-1α), IL-1β, IL-6, CXCL1, and IL-33 in the kidney in AKI was unaffected by PG490-88. In summary, PG490-88 protects against AKI and ATN despite no decrease in tubular apoptosis. The protection of PG490-88 against AKI was associated with a decrease in p-ERK and was independent of MKP-1 and proinflammatory cytokines. In conclusion, PG490-88 protects against cisplatin-induced AKI possibly by decreasing p-ERK. ER -