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
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Published:2023-03-16
Issue:3
Volume:12
Page:729
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ISSN:2076-3921
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Container-title:Antioxidants
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language:en
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Short-container-title:Antioxidants
Author:
Casado-Barragán Felipe1, Lazcano-Páez Geraldine1, Larenas Paulina E.1, Aguirre-Delgadillo Monserrat1, Olivares-Aravena Fernanda1, Witto-Oyarce Daniela1, Núñez-Allimant Camila1, Silva Katherin1, Nguyen Quynh My2, Cárdenas Pilar1, Kassan Modar3ORCID, Gonzalez Alexis A.1ORCID
Affiliation:
1. Institute of Chemisry, Pontificia Universidad Católica de Valparaíso, Valparaíso 2950, Chile 2. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA 3. College of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37917, USA
Abstract
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.
Funder
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) of Chile
Subject
Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology
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