Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells
Chronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-β1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the pro...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/3/729 |
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| author | Felipe Casado-Barragán Geraldine Lazcano-Páez Paulina E. Larenas Monserrat Aguirre-Delgadillo Fernanda Olivares-Aravena Daniela Witto-Oyarce Camila Núñez-Allimant Katherin Silva Quynh My Nguyen Pilar Cárdenas Modar Kassan Alexis A. Gonzalez |
| author_facet | Felipe Casado-Barragán Geraldine Lazcano-Páez Paulina E. Larenas Monserrat Aguirre-Delgadillo Fernanda Olivares-Aravena Daniela Witto-Oyarce Camila Núñez-Allimant Katherin Silva Quynh My Nguyen Pilar Cárdenas Modar Kassan Alexis A. Gonzalez |
| author_sort | Felipe Casado-Barragán |
| collection | DOAJ |
| description | Chronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-β1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the profibrotic phenotype in renal tubular cells. NOX-4 is one of the primary sources of ROS in the diabetic kidney and responsible for the induction of profibrotic factors in collecting duct (CD) cells. The renal medulla is predominantly composed of CDs; in DM, these CD cells are exposed to high glucose (HG) load. Currently there is no published literature describing the expression of these markers in the renal medulla in male and female mice during the early phase of DM, or the role of NOX-4-induced ROS. Our aim was to evaluate changes in transcripts and protein abundances of TGF-β1, fibronectin, and NOX-4 along with ROS levels in renal medullary tissues from male and female mice during a short period of streptozotocin (STZ)-induced type 1 DM and the effect of HG in cultured CD cells. CF-1 mice were injected with or without a single dose of STZ (200 mg/kg) and euthanized at day 6. STZ females showed higher expression of fibronectin and TGF-β1 when compared to control mice of either gender. Interestingly, STZ female mice showed a >30-fold increase on mRNA levels and a 3-fold increase in protein levels of kidney medullary NOX-4. Both male and female STZ mice showed increased intrarenal ROS. In primary cultures of inner medullary CD cells exposed to HG over 48 h, the expression of TGF-β1, fibronectin, and NOX-4 were augmented. M-1 CD cells exposed to HG showed increased ROS, fibronectin, and TGF-β1; this effect was prevented by NOX-4 inhibition. Our data suggest that at as early as 6 days of STZ-induced DM, the expression of profibrotic markers TGF-β1 and fibronectin increases in renal medullary CD cells. Antioxidants mechanisms in male and female in renal medullary tissues seems to be differentially regulated by the actions of NOX-4. |
| first_indexed | 2024-03-11T07:00:53Z |
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| id | doaj.art-c321f66349ae4d139aeeb096498c29e2 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T07:00:53Z |
| publishDate | 2023-03-01 |
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| series | Antioxidants |
| spelling | doaj.art-c321f66349ae4d139aeeb096498c29e22023-11-17T09:18:57ZengMDPI AGAntioxidants2076-39212023-03-0112372910.3390/antiox12030729Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct CellsFelipe Casado-Barragán0Geraldine Lazcano-Páez1Paulina E. Larenas2Monserrat Aguirre-Delgadillo3Fernanda Olivares-Aravena4Daniela Witto-Oyarce5Camila Núñez-Allimant6Katherin Silva7Quynh My Nguyen8Pilar Cárdenas9Modar Kassan10Alexis A. Gonzalez11Institute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileCollege of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37917, USAInstitute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, ChileChronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-β1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the profibrotic phenotype in renal tubular cells. NOX-4 is one of the primary sources of ROS in the diabetic kidney and responsible for the induction of profibrotic factors in collecting duct (CD) cells. The renal medulla is predominantly composed of CDs; in DM, these CD cells are exposed to high glucose (HG) load. Currently there is no published literature describing the expression of these markers in the renal medulla in male and female mice during the early phase of DM, or the role of NOX-4-induced ROS. Our aim was to evaluate changes in transcripts and protein abundances of TGF-β1, fibronectin, and NOX-4 along with ROS levels in renal medullary tissues from male and female mice during a short period of streptozotocin (STZ)-induced type 1 DM and the effect of HG in cultured CD cells. CF-1 mice were injected with or without a single dose of STZ (200 mg/kg) and euthanized at day 6. STZ females showed higher expression of fibronectin and TGF-β1 when compared to control mice of either gender. Interestingly, STZ female mice showed a >30-fold increase on mRNA levels and a 3-fold increase in protein levels of kidney medullary NOX-4. Both male and female STZ mice showed increased intrarenal ROS. In primary cultures of inner medullary CD cells exposed to HG over 48 h, the expression of TGF-β1, fibronectin, and NOX-4 were augmented. M-1 CD cells exposed to HG showed increased ROS, fibronectin, and TGF-β1; this effect was prevented by NOX-4 inhibition. Our data suggest that at as early as 6 days of STZ-induced DM, the expression of profibrotic markers TGF-β1 and fibronectin increases in renal medullary CD cells. Antioxidants mechanisms in male and female in renal medullary tissues seems to be differentially regulated by the actions of NOX-4.https://www.mdpi.com/2076-3921/12/3/729diabetesROSsex differencesmicefibrotic factors |
| spellingShingle | Felipe Casado-Barragán Geraldine Lazcano-Páez Paulina E. Larenas Monserrat Aguirre-Delgadillo Fernanda Olivares-Aravena Daniela Witto-Oyarce Camila Núñez-Allimant Katherin Silva Quynh My Nguyen Pilar Cárdenas Modar Kassan Alexis A. Gonzalez Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells Antioxidants diabetes ROS sex differences mice fibrotic factors |
| title | Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells |
| title_full | Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells |
| title_fullStr | Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells |
| title_full_unstemmed | Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells |
| title_short | Increased Renal Medullary NOX-4 in Female but Not Male Mice during the Early Phase of Type 1 Diabetes: Potential Role of ROS in Upregulation of TGF-β1 and Fibronectin in Collecting Duct Cells |
| title_sort | increased renal medullary nox 4 in female but not male mice during the early phase of type 1 diabetes potential role of ros in upregulation of tgf β1 and fibronectin in collecting duct cells |
| topic | diabetes ROS sex differences mice fibrotic factors |
| url | https://www.mdpi.com/2076-3921/12/3/729 |
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