Abstract Title: Dapagliflozin attenuates loss of Lrp2 to preserve circulating apolipoprotein M and endothelial integrity

Background Sodium-glucose co-transporter inhibitors (SGLT2i) have been found to reduce inflammation and preserve vascular integrity, although no unifying mechanism explains the link between the renal effects of SGLT2i and endothelial barrier function. Apolipoprotein M (ApoM), a lipocalin associated with high-density lipoprotein, is inversely associated with mortality in inflammatory conditions and is critical for maintenance of vascular integrity via sphingosine-1-phosphate (S1P) signaling. We set out to test the hypothesis that pre-treatment with selective SGLT2i dapagliflozin (Dapa) improves vascular integrity in endotoxin (lipopolysaccharide, LPS)-treated mice via the ApoM/S1P pathway. Dapa has well-described clinical benefits in type 2 diabetes mellitus (T2DM), heart failure (HF) and chronic kidney disease.

Methods To test our hypothesis, mice with diet-induced obesity were gavaged with vehicle or Dapa for 4 days prior to LPS (10 mg/kg IP). Mice receiving Dapa restored circulating ApoM levels by increasing proximal tubular Lrp2 compared with vehicle in LPS-treated mice. Proximal tubule-specific knockout of the multi-ligand protein receptor Lrp2 blocked the effect of Dapa on circulating ApoM. In vitro, Dapa stimulated uptake of GFP-ApoM in a Lrp2-dependent manner. In LPS models utilizing ApoM transgenic mice, knockout mice, and S1P receptor 1 and 3 inhibitors, ApoM/S1P signaling was necessary and sufficient for the beneficial effects of Dapa in the LPS model.

Results In the setting of acute inflammation, Dapa maintains levels of Lrp2, leading to preservation of ApoM, which in turn promotes endothelial barrier integrity and improves hemodynamics.

Conclusion Our studies suggest a novel mechanism by which Dapa pre-treatment reduces LPS-induced endothelial leak in an ApoM/S1P-dependent manner and can preserve intravascular volume in the acute inflammatory setting. Dapa preserved cardiac preload, as evidenced by preserved end-diastolic volume index, coronary sinus area, and had an increased right atrial contraction pressure during a severe inflammatory reaction, all of which led to the beneficial effects of Dapa in acute inflammation.