Purchase this article with an account.
J. Petrash, S. Palla, T. M. Harter, T. A. Griest, P. A. Ruzycki, B. G. Reddy; Hyperglycemia-Associated Defects in Aldo-Keto Reductase Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2116.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Aldose reductase (AKR1B1) is thought to play a role in diabetic cataract through production of polyols and activation of the polyol pathway. To test the hypothesis that diabetic eye disease is dependent on polyol accumulation in the lens, we produced lines of transgenic mice that over-express either human aldose reductase (HAR, AKR1B1) or human small intestine reductase (HSIR, AKR1B10). HSIR is functionally identical in virtually all respects to HAR with the notable exception that it is incapable of catalyzing the reduction of glucose to sorbitol.
Reading frames encoding either HAR (AKR1B1) or HSIR (AKR1B10) were placed under transcription control of a hybrid /Δ crystallin promoter element obtained from Lixing Renecker (University of Missouri). Lenses from multiple founder lines produced from each construct, together with nontransgenic controls, were screened for expression levels of the respective AKRs by enzyme activity measurements, Western blotting, and immunohistochemical staining. Effects of hyperglycemia were evaluated histologically following organ culture of lenses in the presence of high glucose with or without an aldose reductase inhibitor. Sorbitol levels were measured enzymatically.
High expression levels of HAR caused lens degeneration in two independent founder lines, whereas lenses from a third HAR transgenic line, characterized by relatively low transgene expression, were morphologically indistinguishable from nontransgenic controls. Lenses from all lines of HSIR transgenic mice were morphologically normal regardless of expression level of the transgene. Although glucose is not a substrate for HSIR, dramatic fiber cell swelling, reminiscent of osmotic stress associated with diabetic cataract, was observed in HSIR transgenic lenses following culture in the presence of high glucose. High glucose-dependent swelling in these lenses was reduced by sorbinil. Unlike the case with HAR transgenics, sorbitol levels were not elevated in HSIR transgenic lenses cultured under high glucose conditions.
This PDF is available to Subscribers Only