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Prevention of tubulin/aldose reductase association delays the development of pathological complications in diabetic rats

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Abstract

In recent studies, we found that compounds derived from phenolic acids (CAFs) prevent the formation of the tubulin/aldose reductase complex and, consequently, may decrease the occurrence or delay the development of secondary pathologies associated with aldose reductase activation in diabetes mellitus. To verify this hypothesis, we determined the effect of CAFs on Na+,K+-ATPase tubulin-dependent activity in COS cells, ex vivo cataract formation in rat lenses and finally, to evaluate the antidiabetic effect of CAFs, diabetes mellitus was induced in Wistar rats, they were treated with different CAFs and four parameters were determinates: cataract formation, erythrocyte deformability, nephropathy and blood pressure. After confirming that CAFs are able to prevent the association between aldose reductase and tubulin, we found that treatment of diabetic rats with these compounds decreased membrane-associated acetylated tubulin, increased NKA activity, and thus reversed the development of four AR-activated complications of diabetes mellitus determined in this work. Based on these results, the existence of a new physiological mechanism is proposed, in which tubulin is a key regulator of aldose reductase activity. This mechanism can explain the incorrect functioning of aldose reductase and Na+,K+-ATPase, two key enzymes in the pathogenesis of diabetes mellitus. Moreover, we found that such alterations can be prevented by CAFs, which are able to dissociate tubulin/aldose reductase complex.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

The study was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica de la Secretaría de Ciencia y Tecnología del Ministerio de Cultura y Educación, as part of the Programa de Modernización Tecnológica (PICT-2018-03206), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), and Secretaría de Ciencia y Técnica de la Universidad Nacional de Río Cuarto. We want to thank Florencia Sgarlatta for English editing.

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Authors and Affiliations

  1. Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, 5800, Córdoba, CP, Argentina

    Juan F. Rivelli Antonelli, Verónica S. Santander, Ayelen D. Nigra, Noelia E. Monesterolo, Gabriela Previtali, Emilianao Primo & César H. Casale

  2. INBIAS CONICET-UNRC, Instituto de Biotecnología Ambiental y Salud, Campus UNRC, Río Cuarto, 5800, Córdoba, CP, Argentina

    Juan F. Rivelli Antonelli, Verónica S. Santander, Ayelen D. Nigra, Noelia E. Monesterolo, Gabriela Previtali, Emilianao Primo & César H. Casale

  3. Instituto de Investigaciones Bioquímicas de Buenos Aires, IIBBA, CONICET – Fundación Instituto Leloir, Av Patricias Argentinas 435, C1405BWE, Buenos Aires, Argentina

    Lisandro H. Otero

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  1. Juan F. Rivelli Antonelli
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  2. Verónica S. Santander
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  3. Ayelen D. Nigra
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  4. Noelia E. Monesterolo
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  5. Gabriela Previtali
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  6. Emilianao Primo
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  7. Lisandro H. Otero
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  8. César H. Casale
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Contributions

All the authors participated substantially in the conception and design of the work, the acquisition, analysis and interpretation of data, as well as in drafting the article or revising it critically to agree on the version to be published. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to César H. Casale.

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Key points

• Treatment of cultured cells with CAFs prevented the formation of the Na+,K+-ATPase/Tub complex and restored NKA activity.

• In vivo treatment of rats with CAFs prevented the development of diabetic complications.

• These results provide the basis for a new approach to regulating aldose reductase activity and thus for designing novel treatment options for diabetes.

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Rivelli Antonelli, J.F., Santander, V.S., Nigra, A.D. et al. Prevention of tubulin/aldose reductase association delays the development of pathological complications in diabetic rats. J Physiol Biochem 77, 565–576 (2021). https://doi.org/10.1007/s13105-021-00820-1

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