Activation of aldose reductase by interaction with tubulin and involvement of this mechanism in diabetic cataract formation
- Juan F. Rivellia,
- Verónica S. Santandera,
- Sofía O. Perettia,
- Noelia E. Monesteroloa,
- Ayelen D. Nigraa,
- Gabriela Previtalia,
- Marina R. Amaidena,
- Carlos A. Arceb,
- Emiliano Primoa,
- Angela T. Lisaa,
- Juan Piec and
- César H. Casalea⇑
- aDepartamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800-Córdoba, Argentina.
- bCentro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), UNC-CONICET, Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000-Córdoba, Argentina.
- cDepartments of Pharmacology Physiology and Pediatrics, Medical School, University of Zaragoza, Zaragoza, Spain.
- Corresponding author: César H. Casale, E-mail:
Our previous studies have shown that high levels of glucose induce inhibition of Na+,K+-ATPase (NKA) via stimulation of aldose reductase (AR), polymerisation of microtubules, and formation of an acetylated tubulin/NKA complex. Inhibition of AR eliminated the effect of high glucose on NKA activity. In this study, we investigated the mechanism of regulation of AR activity by tubulin. Purified tubulin and AR were used. The results indicate that: (i) tubulin and AR interact with each other directly; (ii) tubulin/AR interaction results in a 6-fold increase of AR activity under microtubule growing conditions; (iii) AR interacts preferentially with tubulin that contains 3-nitro-L-tyrosine (3-NTyr); (iv) free tyrosine and 3-nitro-tyrsine are able to block tubulin/AR interaction and thereby prevent AR activation; (v) exposure of cultured COS cells to high glucose concentrations promotes microtubule polymerisation and NKA inhibition, and both these promoting effects are inhibited by addition of free Tyr or 3-NTyr; (vi) treatment of experimental (STZ-induced) diabetic rats with 3-NTyr prevented cataract formation, suggesting that this complication of diabetes involves tubulin/AR interaction and AR activity. Taken together, these findings indicate that AR activity is controlled by association/dissociation of the tubulin/AR complex, that Tyr and 3-NTyr block such effect by preventing tubulin/AR complex formation, and that AR activity can be reduced by 3-NTyr or other compounds that inhibit tubulin/AR interaction.
- Received August 16, 2013.
- Accepted March 30, 2014.
- © 2014 by the American Diabetes Association.
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