Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabeticmouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita+/2 and db/db mice compared with wild-type mice.Mouse proximal tubular cells exposed to high glucose showed significant increase in phosphorylationofAkt andGal-1.We clonedGal-1 promoter and identified the transcription factorAP4asbindingtotheGal-1 promoter to up-regulate its function. Transfection of cells with plasmid carrying mutations in the binding sites of AP4 to Gal-1 promoter resulted in decreased protein function of Gal-1. In addition, inhibition ofGal-1 by OTX-008 showed significant decrease in p-Akt/AP4 and protein-promoter activity of Gal-1 and fibronectin. Moreover, downregulation of AP4 by small interfering RNA resulted in a significant decrease in protein expression and promoter activity ofGal-1.We found that kidney of Gal-12/2 mice express very lowlevels of fibronectin protein. In summary, Gal-1 is highly expressed in kidneys of type 1 and 2 diabetic mice, and AP4 is a major transcription factor that activates Gal-1 under hyperglycemia. Inhibition of Gal-1 by OTX-008 blocks activation of Akt and prevents accumulation ofGal-1, suggesting a novel role ofGal-1 inhibitor as a possible therapeutic target to treat renal fibrosis in diabetes.
Bibliographical noteFunding Information:
This work was supported in part by grants from the American Heart Association, a Merit Review Award from the South Texas Veterans Healthcare System (to S.L.H.), and a U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant 5RO1 DK096119 (to S.M.). The authors declare no conflicts of interest.
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- Renal fibrosis
- Hypoglycemic Agents/administration & dosage
- Diabetes Mellitus, Type 1/complications
- Kidney Tubules, Proximal/drug effects
- HEK293 Cells
- Diabetic Nephropathies/etiology
- Gene Expression Regulation/drug effects
- Promoter Regions, Genetic
- Mice, Inbred C57BL
- Galectin 1/physiology
- Insulin/administration & dosage
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Type 2/complications
- Mice, Knockout
- Glucose/administration & dosage
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural