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P. F. Kador, P. Zhang, J. Randazzo, K. Blessing; Novel Murine Models of Early Onset Diabetes for Investigating Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):110.
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© ARVO (1962-2015); The Authors (2016-present)
It has been reported that diabetic mice and rats differ in their retinal levels of oxidative stress and sorbitol accumulation. Our purpose was to investigate these differences by developing new mouse models of early onset diabetes which address the relationship between hyperglycemia, pericyte degeneration, aldose reductase and the onset of retinal vascular lesions.
Transgenic C57BL mice expressing either green fluorescent protein (SMA-GFP) or human AR (SMA-hAR) in vascular cells expressing smooth muscle actin were crossbred to develop a new colony expressing both attributes. SMA-GFP and SMA-GFP-hAR mice were crossbred with male C57BL/6-Ins2Akita/J mice. All offspring were genotyped using DNA preparations from tail snips amplified by PCR and then analyzed by agarose gel electrophoresis. Retinal and lens sorbitol levels were determined by HPLC. Western Blots using commercially available antibodies were used to measure growth factor and signaling expression in retinas of these mice and diabetic rats.
Genotyping confirmed that all anticipated traits were present in >96% of all offspring from the SMA-GFP, SMA-hAR, and SMA-GFP-hAR colonies. Breeding male heterozygous C57BL/6-Ins2Akita/J mice with these transgenics produced viable offspring that naturally develop diabetes and possessed both hAR and GFP in all capillary pericytes. The Akita transgenics developed diabetes at 8 weeks of age with blood glucose levels > 500 mg/dL for males compared to ca 325 mg/dL for females. Sorbitol levels in neural retinas were higher in C57B/6-Ins2Akita/J-SMA-GFP-hAR mice compared to C57BL/6-Ins2Akita/J-SMA-GFP mice. C57B/6-Ins2Akita/J-SMA-GFP-hAR mice demonstrated retinal b-FGF, IGF-1, TGFβ, P-c-Raf, P-Akt, P-SAPK/JNK, P- 44/42 MAPK expression similar to that observed in diabetic rats. Treatment of rats with aldose reductase inhibitors (ARIs) altered this expression to that observed in the C57BL/6-Ins2Akita/J-SMA-GFP mice where increased hAR expression was absent. Treatment of C57B/6-Ins2Akita/J-SMA-GFP-hAR mice with aldose reductase inhibitors reduced expression to levels observed in rats treated with ARIs.
Diabetic mice expressing hAR demonstrate similar growth factor and signaling to that observed with diabetic rats. These new mouse models of early onset diabetes are valuable tools for assessing the role of AR and hyperglycemia in retinal vascular lesions associated with diabetic retinopathy.
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