title: The water-soluble triptolide derivative PG490-88 protects against cisplatin-induced acute kidney injury.
abstract: 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.
authors.affiliation: Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.) and Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado (H.-J.K., K.R., A.O., Q.W., Z.H., A.J., C.L.E.); and Pulmonary Division, University of Colorado at Denver, Denver, Colorado (I.S.D.).
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ozkok
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: He
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Ivor S
authors.initials: IS
authors.lastname: Douglas
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000737:chemistry; D007677:Kidney Function Tests; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010616:Phenanthrenes / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; C417603:omtriptolide; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin