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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

Hyun-Jung Kim, Kameswaran Ravichandran, Abdullah Ozkok, Qian Wang, Zhibin He, Alkesh Jani, Danica Ljubanovic, Ivor S. Douglas and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics June 2014, 349 (3) 518-525; DOI: https://doi.org/10.1124/jpet.114.213769
Hyun-Jung Kim
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.)
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Kameswaran Ravichandran
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.)
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Abdullah Ozkok
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.)
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Qian Wang
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.)
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Zhibin He
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.)
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Alkesh Jani
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.)
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Danica Ljubanovic
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.)
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Ivor S. Douglas
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.)
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Charles L. Edelstein
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.)
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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.

Footnotes

    • Received February 7, 2014.
    • Accepted April 4, 2014.
  • H.-J.K., K.R., and A.O. contributed equally to the study.

  • C.L.E. was supported by the Veterans Affairs Merit Review Award [Grant 1I01BX001737], and A.O. was supported by fellowships from the Turkish Society of Nephrology and the International Society of Nephrology.

  • dx.doi.org/10.1124/jpet.114.213769.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 3
1 Jun 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Triptolide in AKI

Hyun-Jung Kim, Kameswaran Ravichandran, Abdullah Ozkok, Qian Wang, Zhibin He, Alkesh Jani, Danica Ljubanovic, Ivor S. Douglas and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 518-525; DOI: https://doi.org/10.1124/jpet.114.213769

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Triptolide in AKI

Hyun-Jung Kim, Kameswaran Ravichandran, Abdullah Ozkok, Qian Wang, Zhibin He, Alkesh Jani, Danica Ljubanovic, Ivor S. Douglas and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics June 1, 2014, 349 (3) 518-525; DOI: https://doi.org/10.1124/jpet.114.213769
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