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Abstract: PO0929

Empagliflozin Inhibits Basal and IL1-β-Mediated CCL2 and Endothelin1 Expression in Human Proximal Tubular Cells

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Pirklbauer, Markus, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Bernd, Maximilian, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Fuchs, Lisa, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Staudinger, Petra, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Corazza, Ulrike, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Leierer, Johannes, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Mayer, Gert J., Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
  • Schramek, Herbert, Medical University Innsbruck - Department of Internal Medicine IV (Nephrology and Hypertension), Innsbruck, Tyrol, Austria
Background

SGLT2 inhibitiors (SGLT2i) slow the progression of type II diabetic kidney disease, however, evidence for underlying molecular mechanisms is scarce. As reno-protection is observed promptly after starting SGLT2i, we aimed at investigating pathways involved in early disease pathogenesis.

Methods

human proximal tubular cell (HPTC) culture (HK-2 and RPTEC), microarray hybridization, real-time PCR, ELISA.

Results

Microarray hybridization identified 1263 genes that presented a uniform expression pattern 24h after ligand stimulation: IL1-β-mediated up- and Empagliflocin (Empa) mediated down-regulation in two HPTC lines (n=2, each). Functional annotation of these genes using DAVID enrichment analysis identified 33 pathway clusters. Based on their established involvement in early pathogenesis of diabetic kidney disease, 2 genes of interest, namely CCL2 and endothelin1, that were represented in the two top ranked clusters, have been selected for verification on the mRNA level:
Basal CCL2 mRNA expression was upregulated by IL1-β (10 ng/ml) (15-fold, p<0,01 and 19-fold, p<0,01) but downregulated by Empa (500nM) (0,6-fold, p<0,01 and 0,5-fold, p<0,001) as early as 1h and at least for 24h after ligand stimulation in HK-2 and RPTEC cells, respectively. Coadministration of Empa inhibited IL1-β-mediated CCL2 mRNA expression after 1h (0,2-fold, p<0,01 and 0,2-fold, p<0,01) and 24h (0,2-fold, p<0,001 and 0,6-fold, p<0,01) in HK-2 and RPTEC cells, respectively. Basal endothelin1 mRNA expression was upregulated by IL1-β (3-fold, p<0,001 and 8-fold, p<0,001) but downregulated by Empa (0,3-fold and 0,2-fold, p<0,001 each) as early as 1h and at least for 24h after ligand stimulation in HK-2 and RPTEC cells, respectively. Coadministration of Empa inhibited IL1-β-mediated endothelin1 mRNA expression after 1h (0,2-fold and 0,2-fold, p<0,001 each) and 24h (0,1-fold, p<0,001 and 0,7-fold, ns.) in HK-2 and RPTEC cells, respectively.
In HK-2 cells, Empa inhibited both IL1-β-induced CCL2 (0,24-fold, p<0,001) and basal endothelin1 (0,4-fold, p<0,001) protein expression.

Conclusion

By demonstrating an inhibitory effect of Empa on basal and IL1-β-mediated CCL2 and endothelin1 expression in two independent HPTCs, we present novel evidence for early non-hemodynamic, nephro-protective effects of SGLT2i.