Na/h exchange regulatory factor 1 deficient mice show evidence of oxidative stress and altered cisplatin pharmacokinetics

Authors

Adrienne M. Bushau-Sprinkle, University of Louisville
Michelle T. Barati, University of Louisville Health Sciences Center
Yuxuan Zheng, University of Louisville
Walter H. Watson, University of Louisville
Kenneth B. Gagnon, The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research
Syed Jalal Khundmiri, Howard University College of Medicine
Kathleen T. Kitterman, University of Louisville Health Sciences Center
Barbara J. Clark, University of Louisville
Leah J. Siskind, University of Louisville
Mark A. Doll, University of Louisville
Michael E. Brier, University of Louisville
Susan Coventry, University of Louisville
Eleanor D. Lederer, The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research

Document Type

Article

Publication Date

7-1-2021

Abstract

(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) Re-sults: 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.

Recommended Citation

Bushau-Sprinkle, Adrienne M.; Barati, Michelle T.; Zheng, Yuxuan; Watson, Walter H.; Gagnon, Kenneth B.; Khundmiri, Syed Jalal; Kitterman, Kathleen T.; Clark, Barbara J.; Siskind, Leah J.; Doll, Mark A.; Brier, Michael E.; Coventry, Susan; and Lederer, Eleanor D., "Na/h exchange regulatory factor 1 deficient mice show evidence of oxidative stress and altered cisplatin pharmacokinetics" (2021). College of Medicine Faculty Publications. 83.
https://dh.howard.edu/med_fac/83