MO625INHIBITION OF SGLT-2 CANNOT RESCUE NEPHRIN EXPRESSION IN DIABETIC NEPHROPATHY

Background and Aims Early glomerular damage in diabetes is induced by high blood glucose level (hyperglycemia) which affects the glomerular filtration barrier and leads to proteinuria. Podocyte-specific proteins like the transmembrane protein nephrin form the slit diaphragm that is important for proper function of the glomerular filtration barrier. Sodium-glucose co-transporter 2 (SGLT2) specific proteins are involved in glucose reabsorption in the kidney and maintain the normal glucose level in the blood. Recent studies showed remarkable success of SGLT2-inhibition in patients with diabetic nephropathy. Therefore we wanted to study if hyperglycemia induced reduction of nephrin expression is affected bySGLT-2 inhibition. Therefore we induced hyperglycemia in zebrafish larvae by knockdown of Pancreatic duodenal homeobox 1 (Pdx1) transcription factor and treated zebrafish larvae with Empagliflozin. In parallel we treated Bl/6 mice with streptozotozin and treated them with Empagliflozin. We then analyzed nephrin expression in both model systems. Method Zebrafish is an ideal model to study glomerular diseases, because the zebrafish larvae develops a pronephros with high homology to the human glomerulus. In order to inhibit SLGT-2 after Pdx1-knockdown, we treated both control and diabetic zebrafish larvae with 10µM Empagliflozin from 1dpf to 5dpf. We used a zebrafish line that expresses a fluorescent Vitamin D binding plasma protein Tg(l-fabp:DBP:eGFP) to measure proteinuria by measuring the GFP signal in both retinal and glomerular vessels of 120 hpf larvae. Immunohistochemistry against nephrin was performed using a specific zebrafish antibody. Results Conclusion Despite the promising effects of SLGT-2 inhibitor treatment in patients with diabetic nephropathy the early effects on nephrin expression are not addressed and remain an unchanged problem by this novel treatment option.