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Na⁺-Glucose Transporter-2 Messenger Ribonucleic Acid Expression in Kidney of Diabetic Rats Correlates with Glycemic Levels: Involvement of Hepatocyte Nuclear Factor-1 Expression and Activity

Department of Physiology and Biophysics (H.S.F., G.F.A., M.M.O., M.O.-S., S.B., U.F.M.), Institute of Biomedical Sciences, and Diabetes Unit (K.F.S.M.), Division of Endocrinology and Metabolism, Medical School, University of Sao Paulo, 05505-900 Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Ubiratan Fabres Machado, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1524, 05505-900 Sao Paulo (SP), Brazil. E-mail: ubiratan{at}icb.usp.br.

Mutations in Na⁺-glucose transporters (SGLT)-2 and hepatocyte nuclear factor (HNF)-1 genes have been related to renal glycosuria and maturity-onset diabetes of the young 3, respectively. However, the expression of these genes have not been investigated in type 1 and type 2 diabetes. Here in kidney of diabetic rats, we tested the hypotheses that SGLT2 mRNA expression is altered; HNF-1 is involved in this regulation; and glycemic homeostasis is a related mechanism. The in vivo binding of HNF-1 into the SGLT2 promoter region in renal cortex was confirmed by chromatin immunoprecipitation assay. SGLT2 and HNF-1 mRNA expression (by Northern and RT-PCR analysis) and HNF-1 binding activity of nuclear proteins (by EMSA) were investigated in diabetic rats and treated or not with insulin or phlorizin (an inhibitor of SGLT2). Results showed that diabetes increases SGLT2 and HNF-1 mRNA expression (50%) and binding of nuclear proteins to a HNF-1 consensus motif (100%). Six days of insulin or phlorizin treatment restores these parameters to nondiabetic-rat levels. Moreover, both treatments similarly reduced glycemia, despite the differences in plasma insulin and urinary glucose concentrations, highlighting the plasma glucose levels as involved in the observed modulations. This study shows that SGLT2 mRNA expression and HNF-1 expression and activity correlate positively in kidney of diabetic rats. It also shows that diabetes-induced changes are reversed by lowering glycemia, independently of insulinemia. Our demonstration that HNF-1 binds DNA that encodes SGLT2 supports the hypothesis that HNF-1, as a modulator of SGLT2 expression, may be involved in diabetic kidney disease.

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