*4.2.4 Regulation of SGLT2*

SGLT2 gene is located at chromosome 16 p11.2 and is expressed primarily in renal cortex. Various transcription factors are involved in regulation of SGLT2 such as SP-1, HNF1-alpha, and HNF4A, and their binding sites have been identified on SGLT2 promoter region [28].

High-sodium intake promotes urinary sodium and glucose excretion by increasing plasma adiponectin level through stimulation of peroxisome proliferatoractivated receptor delta in adipose tissue. The enhanced adiponectin downregulates SGLT2 leading to reduced reabsorption of sodium and glucose. Due to hyperglycemia, this mechanism gets dampened in DM. Binding of SP-1 and HNF1-alpha at the promoter site is involved in this regulation [52], while HNF4A participates in glucose-dependent regulation of SGLT2 in alpha cells of the pancreas [31].

Activation of transcription factor NFκB (nuclear factor kappa-light-chainenhancer of activated B cells) downregulates transcription of SGLT2 in the presence of hyperglycemia due to increase in ROS [53]. Sympathetic innervation has been found to be involved in transcriptional upregulation of SGLT2 in the kidney [54].

Posttranscriptional regulation of SGLT2 is yet to be understood well. Recently, it was found that the 17 kDa protein membrane-associated protein 17 (MAP17) upregulates functional activity of SGLT2 in the plasma membrane [55].
