The Molecular Effect of Empagliflozin (SGLT2i) on the Autophagy Pathway in Type 2 Diabetic Mice Model With Diabetic Nephropathy
Abstract
podocytes ameliorates kidney injury in these two animal models,. These data suggest a protective role of Tyro3 against podocyte injury in glomerular disease. Here, we liked to further dissect the mechanisms of Tyro3 in podocytes and develop Tyro3 agonists as potential drugs to treat glomerular disease. Methods: In vitro studies: culture of human podocytes with overexpression or knockdown of Tyro3, western blot, co-immunosprecipitation, and mass spectrometry. In vivo studies: OVE26 diabetic mice and ARDN treated with Tyro3 agonists or vehicle. Kidney histology, albuminuria, and renal function will be assessed in these mice. Results: By immunoprecipitation combined with mass spectrometry analysis we identified TCTP and nicalin as the top Tyro3-interacted proteins. Nicalin is a member of the γ -secretase complex. TCTP is known to inhibit apoptosis through interaction with multiple partners such as p53 and Bax. We showed that Tyro3 interacted with TPTC to induce its phosphorylation and thereby inhibiting apoptosis of podocytes. Tyro3 also interacted with nicalin to induce the cleavage of Tyro3 into a soluble form. Overexpression of soluble Tyro3 inhibits its protective effects of Tyro3 in podocytes. Circulating Tyro3 increased in DKD patients. Therefore, our data suggest that increased soluble Tyro3 in DKD patients could suppress the protective effects of Tyro3 in podocytes, leading to more podocyte injury. In addition, we screened and identified a specific Tyro3 agonist (C10)…
Read the paper
Related studies
- Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol
- Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance
- SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism
- Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors
- Sodium-glucose cotransporter inhibitors: beyond glycaemic control
- Decoding the effects of SGLT2 inhibitors on cardiac arrhythmias in heart failure
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.