Antifibrotic effects of low dose SGLT2 Inhibition with empagliflozin in comparison to Ang II receptor blockade with telmisartan in 5/6 nephrectomised rats on high salt diet - 16/01/22
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Abstract |
To date, the lowest protective SGLT2 inhibitor dose is unknown. We initially performed a dose-response pilot study in normal rats. Based on the results of this pilot 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). The experimental set up was 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). Empagliflozin treatment increased urinary glucose excretion, in parallel to empagliflozin plasma levels, in a dose-dependent manner starting at doses of 1 mg/kg in the pilot study. 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 observed when implementing the standard dose (5 mg/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. In conclusion, the antifibrotic properties of low dose empagliflozin were comparable to a standard dose of telmisartan. The underlying pathways appear to be TGF independent.
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Highlights |
• | The clinical use of SGLT2 inhibitors is sometimes limited by side effects such as ketoacidosis or urinary tract infections. The lowest effective dose, however, is yet not established. |
• | In an initial pilot study, we identified the lowest empagliflozin dose increasing urinary glucose excretion indicating efficacy in healthy rats. |
• | The antifibrotic properties of this low dose of 1 mg/kg empagliflozin – about 10 times lower as currently used - were comparable to a standard dose of telmisartan in 5/6 nephrectomies rats on high salt died. |
• | RNA-sequencing revealed that both telmisartan and empagliflozin exert their cardiac effects on genes involved in vascular cell stability and cardiac iron homeostasis, whereas renal effects involved genes important for endothelial function and oxidative stress. |
Abbreviations : SGLT2, T2DM, sham, 5/6 Nx, HSD, HPLC, H&E, DEGs, Glp1r, Glp2r, Sglt1, Sglt2, Dusp15, Galnt13, Noxo1, Ep300, Sulf2, ANOVA, LSD, TGF, SBP, ACR, PBO, TELM, EMPA, OP1, OP2, Uni-Nx
Keywords : 5/6 nephrectomy, High salt diet, SGLT2 inhibitor, Ang II receptor blockade, Heart fibrosis
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Vol 146
Articolo 112606- Febbraio 2022 Ritorno al numeroBenvenuto su EM|consulte, il riferimento dei professionisti della salute.
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