Back
For best output, select "Paper Size" as "A4" and "Margin" as "0" or "None".
To save or print to PDF, please select Print Destination > Save as PDF, enable Background Graphics under "More Settings", then click "Save".
During the congress, E-Posters will be accessible to all participants on the congress website 24/7, as well as in the E-poster stations in the congress center.
Preparing your E-Poster
Please review the E-Poster format requirements carefully when preparing your E-Poster. Should your E-Poster not meet the mentioned requirements, it may not be displayed as described above.
E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
Please follow the instructions below to input your abstract title.
Abstract titles should be brief and reflect the content of the abstract.
Megalin, a multi-ligand endocytic receptor in proximal tubules (PTs), mediates the uptake of glomerular-filtered lipotoxic proteins, thereby contributing to tubulo-glomerular injury in high-fat diet (HFD)-fed mice (Kuwahara et al., JASN, 2016). This process is characterized by pathological vacuolation in PTs, which results from megalin-dependent autolysosomal dysfunction. Vacuolation is mainly observed in segment 2 of PTs, which is vulnerable to metabolic stress because of its less robust endo-lysosomal system. Although receptor-mediated endocytosis (RME) predominates in segment 1, fluid-phase endocytosis (FPE) is more active in segment 2. The present study investigates the effects of dapagliflozin, a sodium–glucose cotransporter 2 inhibitor, on HFD-induced autolysosomal dysfunction in PTs through its actions on RME and FPE.
RME and FPE in PTs were scrutinized on kidney sections post intravenous injection of fluorescent lysozyme and low-molecular-weight dextran, respectively, in 9-week-old male kidney-specific conditional megalin-knockout mice and littermate controls (n = 7 per group), as well as male C57BL/6J mice receiving dapagliflozin or vehicle for 5 days (n = 5 per group). The glomerular filtration rate (GFR) was also measured using a Transdermal GFR Monitor in C57BL/6J mice under the same experimental conditions. Nine-week-old male C57BL/6J mice were fed an HFD with oral administration of dapagliflozin (1mg/kg body weight/day) or vehicle for 28 days (n = 10 per group). Kidney sections underwent PAS staining, and Image-Pro Plus ver. 7.0 evaluated the vacuolar area/cortical tubular area. Urinary C-megalin, a marker for lysosomal metabolic overload in PTs, was also measured. Renal megalin expression was gauged via immunoblotting, qPCR, and immunohistochemistry. Megalin's endocytic function was assessed by measuring the urinary excretion of α1-microglobulin, an endocytic ligand of megalin. The direct interaction of dapagliflozin with megalin was assayed by using surface plasmon resonance.
In megalin-knockout mice, the uptake of both fluorescent lysozyme and dextran in PTs decreased. Similarly, the administration of dapagliflozin to C57BL/6J mice reduced the uptake of both tracers in PTs without altering the GFR. Dapagliflozin administration significantly reduced the vacuolar area/cortical tubular area and urinary C-megalin excretion in HFD-fed C57BL/6J mice. Although renal megalin expression remained unaltered, urinary α1-microglobulin excretion increased by dapagliflozin administration. Surface plasmon resonance analysis revealed that dapagliflozin has very low affinity for megalin (KD > 1 mM).
Megalin was found to be involved in both RME and FPE in PTs in vivo. Dapagliflozin alleviates HFD-induced, megalin-mediated autolysosomal dysfunction—particularly in segment 2 of PTs—likely by suppressing megalin-dependent RME and, more notably, FPE. Indirect mechanisms likely mediate the inhibitory effects of dapagliflozin on megalin’s endocytic function.
