Abstract
Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC), leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml) in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB) and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-κB suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression through phosphorylated smad3.
Highlights
Diabetic nephropathy is the leading cause of end stage kidney disease and its escalating incidence is a challenge to health systems in both the developed and developing worlds
This begs the question – does this protect the proximal tubular cells from glycotoxicity? Our studies initially looked at whether high glucose altered the expression of the sodium dependent glucose transporters (SGLT) in HK2 cells, a human kidney proximal tubule cell line
The findings suggest that there is no regulation of these glucose transporters in response to a high glucose milieu, as high glucose did not alter the protein expression of SGLT1 or Sodium/glucose cotransporter 2 (SGLT2)
Summary
Diabetic nephropathy is the leading cause of end stage kidney disease and its escalating incidence is a challenge to health systems in both the developed and developing worlds. Sodium/glucose co-transporter 2 inhibitors (SGLT2inh) are promising (not yet on the market) agents used to achieve glycaemic control in type 2 diabetes that have the added advantage of not promoting hyperinsulinaemia, weight gain or inducing hypoglycaemia [2,3]. Their method of action is to block glucose entry into the kidney proximal tubular cell, a process known to be integrally involved in the development of diabetic nephropathy [4,5,6].
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