Endothelial Cell-Specific Overexpression of Endothelial Nitric Oxide Synthase in Ins2Akita Mice Exacerbates Diabetic Nephropathy
Autor: | Thomas J. Prihoda, Mohan Natarajan, Sumathy Mohan, Samy L. Habib, Robert L. Reddick, Krishnan Manickam, Sherry L. Werner, Caroline R. Delma |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
Genetically modified mouse
medicine.medical_specialty Nitric Oxide Synthase Type III Endocrinology Diabetes and Metabolism Kidney Glomerulus 030209 endocrinology & metabolism Mice Inbred Strains Mice Transgenic 030204 cardiovascular system & hematology Article Nephropathy Nitric oxide Diabetic nephropathy 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Endocrinology Enos Internal medicine Diabetes mellitus Internal Medicine medicine Animals Insulin Diabetic Nephropathies chemistry.chemical_classification Reactive oxygen species biology business.industry medicine.disease biology.organism_classification Endothelial stem cell Disease Models Animal Microscopy Electron chemistry Disease Progression Endothelium Vascular business |
Popis: | AIM/HYPOTHESIS: Endothelial dysfunction due to impaired endothelial nitric oxide synthase (eNOS) activity is a key factor implicated in the progression of diabetic nephropathy. Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions. In this study we investigated whether targeted expression of eNOS and enhanced bioavailability of nitric oxide in renal microvascular endothelial cells rescues diabetic nephropathy. In transgenic mice, overexpression of eNOS has been shown to protect against tissue injury; however, the effect of targeted expression of eNOS in the kidney microvasculature has not been examined. METHODS: To determine if overexpression of eNOS in endothelial cells of diabetic mice ameliorates renal lesions, transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type-1 (AK) diabetic mice to generate eNOSTg/AK mice. Kidneys from wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for morphology and reactive oxygen species production; each group was analyzed for blood glucose levels, kidney/body weight and urine albumin/creatinine levels. RESULTS: AK and eNOSTg/AK mice were hyperglycemic. eNOSTg mice unexpectedly showed evidence of glomerular injury with segmental mesangiolysis and occasional microaneurysms. As expected, glomeruli of AK mice showed diabetic changes with matrix expansion and early nodules. Notably, overexpression of eNOS in eNOSTg/AK mice led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to the superoxide generated by the uncoupling of eNOS. CONCLUSION/INTERPRETATION: The eNOSTg/AK model will be useful for elucidating mechanisms that regulate eNOS function and may suggest therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. |
Databáze: | OpenAIRE |
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