N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice
Abstract Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic h...
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15767 |
| _version_ | 1797397572446322688 |
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| author | Ajay Medipally Min Xiao Anjali A. Satoskar Laura Biederman Alana Dasgupta Iouri Ivanov Galina Mikhalina Brad Rovin Sergey V. Brodsky |
| author_facet | Ajay Medipally Min Xiao Anjali A. Satoskar Laura Biederman Alana Dasgupta Iouri Ivanov Galina Mikhalina Brad Rovin Sergey V. Brodsky |
| author_sort | Ajay Medipally |
| collection | DOAJ |
| description | Abstract Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N‐acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF‐ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF‐ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin‐associated increase in SCr and BP but not hematuria. IFTA, TGF‐ß, and ROS in the kidney as well as TNF‐ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients. |
| first_indexed | 2024-03-09T01:13:02Z |
| format | Article |
| id | doaj.art-c1cb8202471a4e6f9369770ce147129e |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:13:02Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-c1cb8202471a4e6f9369770ce147129e2023-12-11T03:20:34ZengWileyPhysiological Reports2051-817X2023-07-011113n/an/a10.14814/phy2.15767N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy miceAjay Medipally0Min Xiao1Anjali A. Satoskar2Laura Biederman3Alana Dasgupta4Iouri Ivanov5Galina Mikhalina6Brad Rovin7Sergey V. Brodsky8Department of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USARochester Regional Health Nephrology Rochester New York USADepartment of Medicine The Ohio State University Wexner Medical Center Columbus Ohio USADepartment of Pathology The Ohio State University Wexner Medical Center Columbus Ohio USAAbstract Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N‐acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF‐ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF‐ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin‐associated increase in SCr and BP but not hematuria. IFTA, TGF‐ß, and ROS in the kidney as well as TNF‐ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.https://doi.org/10.14814/phy2.157675/6 nephrectomyinterstitial fibrosismouse strainN‐acetylcysteine |
| spellingShingle | Ajay Medipally Min Xiao Anjali A. Satoskar Laura Biederman Alana Dasgupta Iouri Ivanov Galina Mikhalina Brad Rovin Sergey V. Brodsky N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice Physiological Reports 5/6 nephrectomy interstitial fibrosis mouse strain N‐acetylcysteine |
| title | N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice |
| title_full | N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice |
| title_fullStr | N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice |
| title_full_unstemmed | N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice |
| title_short | N‐acetylcysteine ameliorates hematuria‐associated tubulointerstitial injury in 5/6 nephrectomy mice |
| title_sort | n acetylcysteine ameliorates hematuria associated tubulointerstitial injury in 5 6 nephrectomy mice |
| topic | 5/6 nephrectomy interstitial fibrosis mouse strain N‐acetylcysteine |
| url | https://doi.org/10.14814/phy2.15767 |
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