Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics
Adrienne M. Bushau-Sprinkle,
Michelle T. Barati,
Yuxuan Zheng,
Walter H. Watson,
Kenneth B. Gagnon,
Syed Jalal Khundmiri,
Kathleen T. Kitterman,
Barbara J. Clark,
Leah J. Siskind,
Mark A. Doll,
Michael E. Brier,
Susan Coventry,
Eleanor D. Lederer
Affiliations
Adrienne M. Bushau-Sprinkle
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Michelle T. Barati
Department of Medicine, Division of Nephrology, University of Louisville, Louisville, KY 40202, USA
Yuxuan Zheng
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Walter H. Watson
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Kenneth B. Gagnon
Division of Nephrology and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Department of Medicine, Dallas, TX 75390, USA
Syed Jalal Khundmiri
Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA
Kathleen T. Kitterman
Department of Medicine, Division of Nephrology, University of Louisville, Louisville, KY 40202, USA
Barbara J. Clark
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA
Leah J. Siskind
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Mark A. Doll
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Michael E. Brier
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
Susan Coventry
Department of Pathology, University of Louisville, Louisville, KY 40202, USA
Eleanor D. Lederer
Division of Nephrology and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Department of Medicine, Dallas, TX 75390, USA
(1) Background: One third of patients who receive cisplatin develop an acute kidney injury. We previously demonstrated the Na/H Exchange Regulatory Factor 1 (NHERF1) loss resulted in increased kidney enzyme activity of the pentose phosphate pathway and was associated with more severe cisplatin nephrotoxicity. We hypothesized that changes in proximal tubule biochemical pathways associated with NHERF1 loss alters renal metabolism of cisplatin or response to cisplatin, resulting in exacerbated nephrotoxicity. (2) Methods: 2–4 month-old male wild-type and NHERF1 knock out littermate mice were treated with either vehicle or cisplatin (20 mg/kg dose IP), with samples taken at either 4, 24, or 72 h. Kidney injury was determined by urinary neutrophil gelatinase-associated lipocalin and histology. Glutathione metabolites were measured by HPLC and genes involved in glutathione synthesis were measured by qPCR. Kidney handling of cisplatin was assessed by a kidney cortex measurement of γ-glutamyl transferase activity, Western blot for γ-glutamyl transferase and cysteine S-conjugate beta lyase, and ICP-MS for platinum content. (3) Results: At 24 h knock out kidneys show evidence of greater tubular injury after cisplatin and exhibit a decreased reduced/oxidized glutathione ratio under baseline conditions in comparison to wild-type. KO kidneys fail to show an increase in γ-glutamyl transferase activity and experience a more rapid decline in tissue platinum when compared to wild-type. (4) Conclusions: Knock out kidneys show evidence of greater oxidative stress than wild-type accompanied by a greater degree of early injury in response to cisplatin. NHERF1 loss has no effect on the initial accumulation of cisplatin in the kidney cortex but is associated with an altered redox status which may alter the activity of enzymes involved in cisplatin metabolism.
