Effects of SGLT2 Inhibition in Human Kidney Proximal Tubular Cells-Renoprotection in Diabetic Nephropathy?

Panchapakesan, Usha, Pegg, Kate, Gross, Simon, Komala, Muralikrishna Gangadharan, Mudaliar, Harshini, Forbes, Josephine, Pollock, Carol and Mather, Amanda (2013) Effects of SGLT2 Inhibition in Human Kidney Proximal Tubular Cells-Renoprotection in Diabetic Nephropathy?. PLoS One, 8 2: e54442.1-e54442.8. doi:10.1371/journal.pone.0054442

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Author Panchapakesan, Usha
Pegg, Kate
Gross, Simon
Komala, Muralikrishna Gangadharan
Mudaliar, Harshini
Forbes, Josephine
Pollock, Carol
Mather, Amanda
Title Effects of SGLT2 Inhibition in Human Kidney Proximal Tubular Cells-Renoprotection in Diabetic Nephropathy?
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-02-04
Sub-type Article (original research)
DOI 10.1371/journal.pone.0054442
Open Access Status DOI
Volume 8
Issue 2
Start page e54442.1
End page e54442.8
Total pages 8
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
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.
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Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
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