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) 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.
Highlights
IntroductionCisplatin, highly efficacious efficaciouschemotherapeutic chemotherapeuticagent, agent,is is used treatmentCisplatin, aa highly used in in thethe treatment of aof awide widevariety varietyofofcommon commonmalignancies malignancies[1,2,3]. [1,2,3].CisplatinCisplatincrosslinks crosslinkswith withpurine purinebases basesininDNA leading to to cell cell death death [2]. [2]
Na/H Exchange Regulatory Factor 1 (NHERF1) knock out (KO) mice to cisplatin-induced acute kidney injury (AKI). This hypothesis was based on the principle that the development of cisplatin tubular injury is dependent on cisplatin transport into tubular cells and that NHERF1 affects the expression and function of epithelial transporters [24,25]. This original study to investigate the effect of NHERF1 deficiency on cisplatin transport and metabolism in proximal tubule has produced several key findings, including changes in kidney redox state, altered activity and localization of enzymes involved in cisplatin metabolism, and differential Pt handling in NHERF1 KO mouse kidneys
NHERF1 deficient kidneys exhibit evidence of underlying oxidative stress manifested by a higher level of oxidized glutathione and altered metabolic response to cisplatin manifested by the lack of increase in GGT activity and altered CCBL localization
Summary
IntroductionCisplatin, highly efficacious efficaciouschemotherapeutic chemotherapeuticagent, agent,is is used treatmentCisplatin, aa highly used in in thethe treatment of aof awide widevariety varietyofofcommon commonmalignancies malignancies[1,2,3]. [1,2,3].CisplatinCisplatincrosslinks crosslinkswith withpurine purinebases basesininDNA leading to to cell cell death death [2]. [2]. Highly efficacious efficaciouschemotherapeutic chemotherapeuticagent, agent,is is used treatment. Aa highly used in in thethe treatment of aof awide widevariety varietyofofcommon commonmalignancies malignancies[1,2,3]. [1,2,3].Cisplatin. DNA leading to to cell cell death death [2]. Becausecisplatin cisplatinshows showsits its DNA and and inhibits inhibits DNA. DNA synthesis, synthesis, leading most potent cell toxicity in highly proliferative cells, the mechanism for its dose-dependent most potent cell toxicity in highly proliferative cells, the mechanism for its dose-dependand cumulative nephrotoxicity remain largely. Ent and cumulative nephrotoxicity remain largelyunexplained unexplained[1,2,3]
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