Kidney Week

Abstract: TH-PO264

Genetic and Pharmacologic Blockade of Prostaglandin Transporter Attenuates Cisplatin Nephrotoxicity

Session Information

• AKI Basic: Inflammation and Transcription
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Fisher, Molly, Albert Einstein College of Medicine, Bronx, New York, United States

Molly Fisher,

• Pai, Victor J, Albert Einstein College of Medicine, Bronx, New York, United States

Victor J Pai,

• Lu, Run, Albert Einstein College of Medicine, Bronx, New York, United States

Run Lu,

• Schuster, Victor L., Albert Einstein College of Medicine, Bronx, New York, United States

Victor L. Schuster,

Background

Cisplatin (CP) is used to treat a variety of malignancies but nephrotoxicity limits its use. CP nephrotoxicity is characterized by renal vasoconstriction and proximal tubular damage. Underlying molecular mechanisms include inflammation, reactive oxygen species, and apoptotic pathways. Prostaglandins have been shown to be cytoprotective in many tissues including the kidney. Prostaglandins are metabolized by the prostaglandin transporter, PGT. We have developed a PGT knockout mouse and a high-affinity PGT inhibitor, PV02076 (“PV”). Both have been shown to raise endogenous levels of PGE₂ and may be useful therapeutically. We hypothesized that genetic and pharmacologic blockade of PGT would prevent CP nephrotoxicity.

Methods

PGT wildtype and knockout mice were given a single dose of CP 20mg/kg intraperitoneally (IP). C57BL/6 wildtype mice were given vehicle or PV 20mg/kg IP 24 and 1 hour prior to, 24 and 48 hours after, one dose of CP 20mg/kg IP. All mice were sacrificed 72 hours after CP. Renal function was evaluated by serum creatinine, cystatin C, KIM-1 immunohistochemistry, and tissue histology by tubular injury score. Quantitative polymerase chain reaction (Q-PCR) and serum cytokine dot-blot assay were used to identify differences in the expression of inflammatory, oxidative stress, and apoptotic genes. TUNEL assay was performed to assess for cell apoptosis. Urine PGE₂ levels were measured by ELISA.

Results

Urine PGE₂ excretion was increased in KO and PV-treated mice, confirming blockade of PGE₂ metabolism. KO mice had reduced serum creatinine after CP. Pharmacologic blockade of PGT with PV significantly attenuated CP nephrotoxicity as assessed by serum biomarkers of renal injury (creatinine, cystatin C) and histologic measurements of tubular injury and cell apoptosis (KIM-1, tubular injury score, TUNEL assay). Serum biomarkers (TNF-alpha) and renal gene expression studies (IL-6, IL-1beta, bcl2, SOD-1, SOD-2) revealed decreased inflammation, apoptosis, and oxidative stress in CP mice given PV.

Conclusion

Genetic and pharmacologic blockade of PGT attenuates cisplatin nephrotoxicity. We hypothesize the mechanism involves PGE₂-mediated vasodilation and/or cytoprotection through reduction of inflammation, oxidative stress, and apoptosis. Pharmacologic blockade of PGT may be a novel renoprotective strategy for cisplatin nephrotoxicity.

Funding

• Other NIH Support