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Abstract: PO2030

Antifibrotic Effects of Low-Dose SGLT-2 Inhibition in Comparison to Standard Angiotensin II Receptor Blockade in 5/6 Nephrectomised Rats on a High-Salt Diet

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Zeng, Shufei, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Delic, Denis, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Xiong, Yingquan, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Chu, Chang, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Luo, Ting, Jinan University First Affiliated Hospital, Guangzhou, Guangdong, China
  • Xiao-Yi, Chen, Jinan University First Affiliated Hospital, Guangzhou, Guangdong, China
  • Gaballa, Mohamed Mahmoud Salem Ahmed, Universitatsklinikum Mannheim, Mannheim, Germany
  • Xue, Yao, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Chen, Xin, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Cao, Yaochen, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Hasan, Ahmed A., Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
  • Frankenreiter, Sandra, Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany
  • Yin, Lianghong, Jinan University First Affiliated Hospital, Guangzhou, Guangdong, China
  • Krämer, Bernhard K., Universitatsklinikum Mannheim, Mannheim, Germany
  • Klein, Thomas, Boehringer Ingelheim International GmbH, Ingelheim, Rheinland-Pfalz, Germany
  • Hocher, Berthold, Universitatsklinikum Mannheim, Mannheim, Baden-Württemberg, Germany
Background

The lowest protective SGLT2 inhibitor dose is not well established.

Methods

We performed a dose-response pilot study. Based on the results of this study we compared the cardio-renal effects of the SGLT-2 inhibitor empagliflozin with placebo or telmisartan in rats with 5/6 nephrectomy (5/6 Nx) on a high salt diet (HSD), as follows: Sham operation (Sham) with normal diet and placebo; 5/6 Nx with 2% HSD and placebo; 5/6 Nx with HSD and empagliflozin (0.6 mg/kg/day, bid); 5/6 Nx with HSD and telmisartan (5 mg/kg/day, qd).

Results

Empagliflozin treatment increased urinary glucose excretion in parallel to empagliflozin plasma levels in a dose-dependent manner starting at doses of 1 mg/kg. 5/6Nx rats on HSD treated with this low empagliflozin dose showed significantly reduced cardiac (-34.85%; p<0.05) and renal (-33.68%; p<0.05) fibrosis in comparison to 5/6Nx rats on HSD treated with placebo. These effects were comparable to the effects of a standard dose (5mg/kg/day) of telmisartan (cardiac fibrosis: -36.37%; p<0.01; renal fibrosis; -43.96%; p<0.01). RNA-sequencing followed by confirmatory qRT-PCR revealed that both telmisartan and empagliflozin exert their cardiac effects on genes involved in vascular cell stability and cardiac iron homeostasis, whereas in the kidneys expression of genes involved in endothelial function and oxidative stress were differentially expressed. Urinary adenosine excretion, a surrogate marker of the tubuloglomerular feedback (TGF) mechanism, was not affected.

Conclusion

The antifibrotic properties of low dose empagliflozin were comparable to a standard dose of telmisartan. The underlying pathways seem to be TGF independent.

Funding

  • Commercial Support