Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model
Summary: Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-09-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222011592 |
| _version_ | 1818496985518309376 |
|---|---|
| author | Lashodya V. Dissanayake Adrian Zietara Vladislav Levchenko Denisha R. Spires Mariana Burgos Angulo Ashraf El-Meanawy Aron M. Geurts Melinda R. Dwinell Oleg Palygin Alexander Staruschenko |
| author_facet | Lashodya V. Dissanayake Adrian Zietara Vladislav Levchenko Denisha R. Spires Mariana Burgos Angulo Ashraf El-Meanawy Aron M. Geurts Melinda R. Dwinell Oleg Palygin Alexander Staruschenko |
| author_sort | Lashodya V. Dissanayake |
| collection | DOAJ |
| description | Summary: Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To explore how hypouricemia can lead to kidney damage, we created a rat model with the genetic ablation of the Xdh gene on the Dahl salt-sensitive rat background (SSXdh−/−). SSXdh−/− rats lacked UA and exhibited impairment in growth and survival. This model showed severe kidney injury with increased interstitial fibrosis, glomerular damage, crystal formation, and an inability to control electrolyte balance. Using a multi-omics approach, we highlighted that lack of Xdh leads to increased oxidative stress, renal cell proliferation, and inflammation. Our data reveal that the absence of Xdh leads to kidney damage and functional decline by the accumulation of purine metabolites in the kidney and increased oxidative stress. |
| first_indexed | 2024-12-10T18:39:29Z |
| format | Article |
| id | doaj.art-e4f8acdf104a4bc3a8101254fea60d36 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-10T18:39:29Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-e4f8acdf104a4bc3a8101254fea60d362022-12-22T01:37:42ZengElsevieriScience2589-00422022-09-01259104887Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat modelLashodya V. Dissanayake0Adrian Zietara1Vladislav Levchenko2Denisha R. Spires3Mariana Burgos Angulo4Ashraf El-Meanawy5Aron M. Geurts6Melinda R. Dwinell7Oleg Palygin8Alexander Staruschenko9Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USADepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USADivision of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33602, USA; James A. Haley Veterans' Hospital, Tampa, FL 33612, USA; Corresponding authorSummary: Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To explore how hypouricemia can lead to kidney damage, we created a rat model with the genetic ablation of the Xdh gene on the Dahl salt-sensitive rat background (SSXdh−/−). SSXdh−/− rats lacked UA and exhibited impairment in growth and survival. This model showed severe kidney injury with increased interstitial fibrosis, glomerular damage, crystal formation, and an inability to control electrolyte balance. Using a multi-omics approach, we highlighted that lack of Xdh leads to increased oxidative stress, renal cell proliferation, and inflammation. Our data reveal that the absence of Xdh leads to kidney damage and functional decline by the accumulation of purine metabolites in the kidney and increased oxidative stress.http://www.sciencedirect.com/science/article/pii/S2589004222011592Biological sciencesMolecular physiologyMolecular biology |
| spellingShingle | Lashodya V. Dissanayake Adrian Zietara Vladislav Levchenko Denisha R. Spires Mariana Burgos Angulo Ashraf El-Meanawy Aron M. Geurts Melinda R. Dwinell Oleg Palygin Alexander Staruschenko Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model iScience Biological sciences Molecular physiology Molecular biology |
| title | Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| title_full | Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| title_fullStr | Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| title_full_unstemmed | Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| title_short | Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| title_sort | lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model |
| topic | Biological sciences Molecular physiology Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222011592 |
| work_keys_str_mv | AT lashodyavdissanayake lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT adrianzietara lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT vladislavlevchenko lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT denisharspires lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT marianaburgosangulo lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT ashrafelmeanawy lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT aronmgeurts lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT melindardwinell lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT olegpalygin lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel AT alexanderstaruschenko lackofxanthinedehydrogenaseleadstoaremarkablerenaldeclineinanovelhypouricemicratmodel |