Nucleosome Positioning and Gene Regulation of the SGLT2 Gene in the Renal Proximal Tubular Epithelial Cells

Abstract

Filtered glucose is mostly reabsorbed by sodium-glucose cotransporter 2 (SGLT2) in the proximal tubules. SGLT2 is predominantly expressed in the human kidney. However, the regulatory mechanisms for gene expression in the human kidney remain unclear. We in this work elucidated the transcriptional regulatory mechanisms for the gene by nucleosome occupancy in the promoter region. Expressions of SGLT2 mRNA and protein were markedly weaker in human kidney-derived HK-2 cells than the human kidney. The nucleosome occupancy level in the promoter region was low in the kidney, but high in HK-2 cells. A treatment with a histone deacetylase inhibitor trichostatin A (TSA) decreased nucleosome occupancy in the promoter region and increased expression levels in HK-2 cells. The upregulation of expression by histone acetylation was accompanied by a higher binding frequency of hepatocyte nuclear factor (HNF) 1, a transcriptional modulator of in the human kidney, to the promoter region. The transfection of a HNF1 expression plasmid into HK-2 cells resulted in the upregulation of SGLT2 mRNA expression in the presence of TSA, but not in the treatment of dimethylsulfoxide as a control. Nucleosome occupancy in the promoter region was markedly higher in the liver and small intestine than the kidney. Our results indicate that tissue-specific nucleosome occupancy plays an important role in the regulation of gene expression via HNF1 binding at the promoter region.

Direct evidence of proximal tubular proliferation in early diabetic nephropathy

“…This is inconsistent with previous studies reporting the upregulation of both SGLT2 and GLUT2 expression in the primary culture of urine-derived proximal tubular epithelia cells from diabetic patients 26 . As proximal tubular epithelia are highly polarized cells under normal conditions in vivo, the expression patterns and functions of membrane transporters are different between in vitro cultured conditions and in vivo physiological conditions 13 , 27 , which may be problematic for the analysis of diabetic conditions in vitro . For example, SGLT2 expression is observed at the apical membrane of tubular epithelia in vivo , but glucose transport is reduced in in vitro cultured conditions even if SGLT2 mRNA is overexpressed in transfected oocytes 28 .…”

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

“…HNF1A-MODY has been associated with a lower renal threshold for glucose and glucosuria [ 3 , 29 , 49 , 50 ], which could result from insulin deficiency or be a direct effect of HNF1A through reduced renal expression of SLC5A2 (also known as SGLT2 for sodium–glucose cotransporter 2) [ 50 , 51 ], a key transporter involved in tubular glucose reabsorption. In vitro studies indicate that the postprandial insulin surge enhances glucose reabsorption in kidneys [ 52 ].…”

High salt diet‐induced proximal tubular phenotypic changes and sodium‐glucose cotransporter‐2 expression are coordinated by cold shock Y‐box binding protein‐1

“…One possible explanation to this development is the involvement of YB‐1 in the translational regulation of the SGLT2 transcripts. Sglt2 transcripts are regulated by SP1, HNF1α and HNF4α 50 . In vitro translation experiments confirm that YB‐1 inhibits translation of Sglt2 mRNA.…”

“…Sglt2 transcripts are regulated by SP1, HNF1α and HNF4α. 50 In vitro translation experiments confirm that YB-1 inhibits translation of Sglt2 mRNA. Intake of 8% HSD for 24 weeks also leads to reduced SGLT2 expression of WT mice through the regulation of the PPARδ-SGLT2 pathway.…”