Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics
(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 nephr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/7/1036 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adrienne M. Bushau-Sprinkle |
| collection | DOAJ |
| description | (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. |
| first_indexed | 2024-03-10T09:59:46Z |
| format | Article |
| id | doaj.art-80af17770fc1407e803db6c50261bff5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T09:59:46Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-80af17770fc1407e803db6c50261bff52023-11-22T02:04:00ZengMDPI AGAntioxidants2076-39212021-06-01107103610.3390/antiox10071036Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin PharmacokineticsAdrienne M. Bushau-Sprinkle0Michelle T. Barati1Yuxuan Zheng2Walter H. Watson3Kenneth B. Gagnon4Syed Jalal Khundmiri5Kathleen T. Kitterman6Barbara J. Clark7Leah J. Siskind8Mark A. Doll9Michael E. Brier10Susan Coventry11Eleanor D. Lederer12Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, Division of Nephrology, University of Louisville, Louisville, KY 40202, USADepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADivision 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, USADepartment of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USADepartment of Medicine, Division of Nephrology, University of Louisville, Louisville, KY 40202, USADepartment of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USADepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USADepartment of Pathology, University of Louisville, Louisville, KY 40202, USADivision 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.https://www.mdpi.com/2076-3921/10/7/1036cisplatin nephrotoxicityredox statusacute kidney injury |
| spellingShingle | 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 Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics Antioxidants cisplatin nephrotoxicity redox status acute kidney injury |
| title | Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics |
| title_full | Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics |
| title_fullStr | Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics |
| title_full_unstemmed | Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics |
| title_short | Na/H Exchange Regulatory Factor 1 Deficient Mice Show Evidence of Oxidative Stress and Altered Cisplatin Pharmacokinetics |
| title_sort | na h exchange regulatory factor 1 deficient mice show evidence of oxidative stress and altered cisplatin pharmacokinetics |
| topic | cisplatin nephrotoxicity redox status acute kidney injury |
| url | https://www.mdpi.com/2076-3921/10/7/1036 |
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