Superexpressão de <i>Slc2a2</i>/GLUT2 induzida por alta concentração de glicosse em células tubulares renais IRPTC envolve ativação de HNF4A e FOXA2 mediada por AKT

Abstract

LINS, B. B. High glucose concentration-induced overexpression of Slc2a2/GLUT2 in renal tubular cells involves AKT-mediated activation of HNF4A and FOXA2. 2015. 73 p. Masters thesis (Human Physiology) – Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, 2015. Glucose filtrated load is rapidly reabsorbed in renal proximal tubule by the coordinate action of the glucose transporters SGLT2 (sodium: glucose cotransporter 2, codified by Slc5a2 gene) in the apical membrane, and GLUT2 (facilitative glucose transporter 2, codified by Slc2a2 gene), in the basolateral membrane. In diabetes, renal glucose reabsorption increases; that involves overexpression of the glucose transporters, and is reversed by insulin therapy. The transcription factors HNF (hepatocyte nuclear factor) 1A and 4A, and FOXA2 (forkhead box protein A2) have been proposed as modulators of Slc2a2 gene expression. The AKT protein is an important mediator of insulin action, and has been described as able to activate FOXA2. Independent and clear effect of high concentration of glucose or insulin upon the regulation of these genes is unknown. The present study investigates in immortalized rat proximal tubule cells the effects of high glucose (25 mM) and insulin (100 nM) concentrations upon the Slc2a2/GLUT2 and Slc5a2/SGLT2 expression, as well as the participation of AKT, HNF1A, HNF4A and FOXA2. No regulation of Slc5a2/SGLT2 was observed. On the other hand, 25 mM glucose increased the expression of Slc2a2 mRNA and GLUT2 protein, which was accompanied by increased HNF4A and FOXA2 binding in the Slc2a2 promoter, in an AKT-mediated way. Insulin reversed the Slc2a2 mRNA regulation, but did not alter GLUT2 content. In summary, the results reveal that high glucose concentration induces Slc2a2/GLUT2 overexpression in renal proximal tubule cells, which may participate in the development of diabetic nephropathy. Key-words: AKT. GLUT2. SGLT2. HNF1A. HNF4A. FOXA2.