[Background] Podocytes form the essential components of the glomerular filtration barrier and have a critical role in diabetic kidney disease (DKD). Currently, mounting evidence suggests that glucagon-like peptide 1 receptor agonists (GLP-1RAs), anti-diabetic drugs, have beneficial effects on DKD. However, direct effects of GLP-1RAs on diabetic podocyte injury remain unknown. We investigated whether exendin-4, a GLP-1RA, attenuates hyperglycemia-induced podocytes injury using cultured podocytes and DKD in rat models of type 1 diabetes, and if so mechanism of its beneficial effects. [Methods and Results] Cultured podocytes were exposed to media containing normal (NG; 5 mmol/L) or high glucose (HG; 25 mmol/L) for one week in the presence or absence of exendin-4 (10 nmol/L). HG increased podocytes apoptosis and reduced mRNA expression of novel podocyte markers, synaptopodin and Wilms tumor 1 (WT1). Exendin-4 reduced podocytes apoptosis and restored these mRNA expression, however, these protective effects were attenuated by the co-treatment with wortmannin, a PI3 kinase inhibitor. Exendin-4 also preserved Bcl2 and reduced Bax, protein expression. In in vivo study using rat models of streptozotocin-induced type 1 diabetes, exendin-4 suppressed impaired plasma creatinine levels, mesangial expansion, and preserved WT-1-positive podocytes without any changes of plasma glucose levels. [Conclusion] Exendin-4 attenuates hyperglycemia-induced podocyte injury through PI3 kinase signaling pathway, leading to improvement of DKD.
