(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.