Empagliflozin Protects Kidney by Preventing Autophagic Stagnation via Reducing Megalin-Mediated Reabsorption of Lipotoxic Albumin

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Background: Evidence from clinical studies such as DAPA-CKD and EMPA-KIDNEY trials suggests that sodium glucose cotransporter 2 (SGLT2) inhibitors confer renal protection regardless of the presence of diabetes, although the underlying mechanisms remain unclear. Methods: We investigated the following aspects: 1) the impact of empagliflozin (EMPA) on lipotoxicity in kidney proximal tubular epithelial cells (PTECs) in both wildtype and inducible megalin knockout mice, 2) the effect of EMPA on albumin reabsorption in PTECs, 3) the influence of EMPA on autophagic activity, and 4) the effect of EMPA on ischemia-reperfusion injury (IRI) when autophagy and/or megalin are blocked. Results: High-fat diet (HFD) induced the formation of cytosolic vacuoles (enlarged lysosomes containing phospholipids) in PTECs, which was alleviated by EMPA. Since vacuolar formation was rarely observed in HFD-fed inducible megalin knockout mice, we assessed megalin-mediated fluorescent albumin reabsorption in PTECs. HFD led to hyperreabsorption of albumin in both S1-2 and S3 segments, which was restored by EMPA. Subsequently, we measured plasma levels of 24 fractions of free fatty acids bound to albumin. EMPA improved the imbalanced lipoquality induced by HFD. Furthermore, employing inducible Atg5 knockout mice and GFP-MAP1LC3 transgenic mice, we found that EMPA mitigated the HFD-induced increase in autophagic demand and alleviated the stagnation of autophagy. Finally, we aimed to determine whether the reduced reabsorption of lipotoxic albumin and restoration of autophagic flux by EMPA improve the HFDinduced susceptibility to ischemic stress. The renoprotective effect of empagliflozin against IRI-induced acute kidney injury was attenuated when megalin and/or autophagy were blocked. Conclusions: The reduction of toxic albumin reabsorption and prevention of autophagic stagnation in PTECs may be crucial for SGLT2 inhibition-mediated renoprotection. Funding: Commercial Support - Japan Boehringer Ingelheim

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