TUBULIN REGULATES TWO KEY ENZYMES IN DIABETES MELLITUS: ALDOSE REDUCTASE AND NA+, K+-ATPASE

RIVELLI ANTONELLI, J.F.; CASALE C.H; OCHOA A.N.; SANTANDER V.S.

Parana

Congreso; Sociedad Argentina de Investigación en Bioquímica y Biología Molecular LIV Reunión Anual; 2018

SAIB

Among the main pathogenic pathways of diabetes was reported the activation of the enzyme aldose reductase (AR) and the inhibition of the enzyme Na+,K+-ATPase (NKA). In our laboratory, we describe a new mechanism of regulation of AR activity by tubulin (Tub) that leads to the regulation of NKA. Previously, we demonstrate that Tub forms a complex with AR increasing its activity when this Tub/AR complex is incorporated into a microtubule. In this work, we demonstrate that Tub/AR interaction and subsequent activation of AR is prevented in vitro by phenolic acid derivatives (CAFs). In cell cultures and human erythrocytes, exposed to high concentrations of glucose, we showed that glucose induces the activation of AR, increase in the polymerization of Tub and formation of Tub/AR complex. Because of these changes inhibition of NKA activity and decrease of erythrocyte deformability was observed. Similar results can be found in erythrocytes from diabetic subjects. On the other hand, in rat lenses exposed to high concentrations of glucose we observed the development of diabetic cataracts and the activation of the AR enzyme. All these effects of high glucose concentrations can be prevented in the presence of CAFs, because they prevent the Tub/AR interaction. Finally, in streptozotocin-induced diabetic rats we found that the CAFs can prevent the development of diabetic cataracts, the reduction of erythrocyte deformability and arterial hypertension. These results allow us to postulate a new mechanism of regulation of enzymatic activities AR and NKA by tubulin that explain the regulation of both enzymes associated with the development of secondary pathologies of diabetes.