385-P: Effects of Ertugliflozin on Podocyte in High-Fat Diet–Induced Diabetic Kidney Disease Model, In Vivo and In Vitro

Abstract

Early stage of diabetic kidney disease (DKD) involves loss of podocytes, consequently causing albuminuria. SGLT2 inhibitors demonstrated renoprotective effects in DKD, but the mechanism for protection in early DKD is unclear. Here, we investigated the effects of ertugliflozin in high-fat diet (HFD) -induced DKD model, in vivo and in vitro. 5-week-old male C57BL/6J mice were supplemented with HFD for 24 weeks to develop HFD-induced DKD. Ertugliflozin was administrated orally by pre-mixing with HFD for 16 weeks. We evaluated body weight, random blood glucose levels, albuminuria and glucose and insulin tolerance test were performed at 12 weeks after ertugliflozin administration. The renal cortex was collected for histologic examination and SGLT2 expression on podocytes were measured. Albuminuria was significantly decreased in ertugliflozin group compared with HFD group at 12 weeks of ertugliflozin administration (p=0.011) . Body weight, random and fasting blood glucose was not significantly different between HFD group. Glucose and insulin tolerance test showed significant improvement in ertugliflozin group compared with HFD group at 12 weeks (p=0.0004) . In immunohistochemistry studies, glomerular volume and mesangial expansion were attenuated in the ertugliflozin group by 27.6% and 27.8% respectively, compared to HFD group (p=0.002 and p=0.005, respectively) . Glomerular basement membrane thickness was decreased by 45.4% in ertugliflozin group compared to HFD group (p=0.0004) . Significant increase of SGLT2 mRNA expression by 1.6-4.8 fold after 24 hour-albumin expose was observed and SGLT2 protein was increased 1.1-1.3 fold compared to control. Ertugliflozin attenuated diabetic kidney disease in HFD-induced DKD by mitigating glomerular integrity, preserving podocyte morphology, with decreased albuminuria. Upregulation of SGLT2 in podocyte in albuminuric DKD could be suggested as possible target for renoprotective action of SGLT2 inhibitor. Disclosure H.Kim: None. B.Cha: None. H.Lee: None. B.Lim: None. H.Choi: None. E.Kang: None. Y.Kim: None. R.Kim: None. S.Lee: None. Y.Yang: None. H.Park: None. N.Jeon: None. M.Lee: None. Y.Lee: None. Funding Severance Hospital Research fund for Clinical excellence (SHRC) (C-2021-0007)