Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics
| Autor: | Susan Coventry, Kenneth B. Gagnon, Michelle T. Barati, Leah J. Siskind, Yuxuan Zheng, Walter H. Watson, Adrienne M. Bushau-Sprinkle, Syed J. Khundmiri, Mark A. Doll, Kathleen Kitterman, Barbara J. Clark, Eleanor Lederer, Michael E. Brier |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Physiology Clinical Biochemistry redox status RM1-950 Lipocalin Pentose phosphate pathway medicine.disease_cause Biochemistry Article Nephrotoxicity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Molecular Biology Cisplatin Kidney Acute kidney injury cisplatin nephrotoxicity Cell Biology Glutathione medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry acute kidney injury 030220 oncology & carcinogenesis Therapeutics. Pharmacology Oxidative stress medicine.drug |
| Zdroj: | Antioxidants Antioxidants, Vol 10, Iss 1036, p 1036 (2021) Volume 10 Issue 7 |
| ISSN: | 2076-3921 |
| Popis: | (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. |
| Databáze: | OpenAIRE |
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