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Abstract: TH-PO226

Therapeutic Modulation by Combined SLGT2 and ACE Inhibition of Glomerular Filtration in Streptozotocin (STZ)-Diabetic Mice In Vivo

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Kroeger, Hannah, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Kessel, Friederike, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Sradnick, Jan, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Todorov, Vladimir T., Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Gembardt, Florian, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Hugo, Christian, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany

Group or Team Name

  • AG Hugo
Background

Diabetic kidney disease is the leading cause of end-stage renal disease in the Western world. SGLT2 inhibitors, besides ACE inhibitors show renoprotective effects in chronic kidney disease. The underlying renoprotective mechanism of combined SGLT2 inhibition and ACE inhibition therapy is not completely understood. Therefore, we aimed to investigate directly via intravital microscopy the hemodynamic changes in single glomeruli of diabetic mice treated with ACE and/or SGLT2 inhibitors.

Methods

Male C57BL/6 mice were injected with streptozotocin to induce type 1 diabetes. After five weeks of diabetes, mice were treated with enalapril, empagliflozin, or enalapril/empagliflozin for three days. We used longitudinal in vivo imaging to evaluate single nephron GFR (snGFR) and afferent as well as efferent arteriole diameter width during ACE and/or SGLT2 inhibition.

Results

The STZ-diabetic mice showed significant hyperfiltration (control 1003.0 ± 190.5 µl/min/100g b.w vs. diabetic 1329.4 ± 309.6 µl/min/100g b.w., p<0.05). Enalapril treatment led to a reduction of snGFR and significant efferent arteriole dilation (12.55 ± 1.46 µm vs. control 11.92 ± 1.04 µm, p<0.05) but did not affect afferent arteriole width. Reduced snGFR in diabetic mice as induced by empagliflozin was accompanied by afferent arteriole vasoconstriction (11.19 ± 2.55 µm vs. control 12.35 ± 1.32 µm, p<0.05) but no changes of the efferent arteriole width. Unexpectedly, combined treatment with enalapril/empagliflozin reduced snGFR without any significant alteration in afferent or efferent arteriole diameter width.

Conclusion

SGLT2 and ACE inhibitors appear as beneficial hemodynamic regulators of glomerular filtration during early stages of diabetes mellitus by regulating respectively the afferent and the efferent arteriole contractility. The underlying beneficial mechanisms of the combination therapy need further investigation.