Podocyte apoptosis induced by hyperglycemia is considered a critical factor in the development of diabetic nephropathy. Recent studies have implicated Notch signaling in podocyte apoptosis; however, its regulatory mechanisms are not fully understood. In this study, we found that high-glucose treatment increased Notch1 and Jagged-1 expression, the transcriptional activity of Hes, and podocyte apoptosis, and decreased the expression of coactivator-associated arginine methyltransferase 1 (CARM1) in rat podocytes. Transient transfection of CARM1 reversed high-glucose-induced Notch1 expression, the transcriptional activity of Hes, and podocyte apoptosis. Moreover, the silencing of CARM1 using siRNA increased Notch1 expression, the transcriptional activity of Hes, and podocyte apoptosis. However, the Glu(266)-mediated enzymatic activity of CARM1 was not necessary for Notch signaling activation and podocyte apoptosis. Here, we demonstrate that AMP-activated protein kinase alpha (AMPKα) and cannabinoid receptor 1 (CB1R) are regulated by CARM1 and that high-glucose-induced podocyte apoptosis is mediated by a CARM1-AMPKα-Notch1-CB1R signaling axis. We also show that high-glucose-induced CARM1 downregulation is due to ubiquitination-dependent CARM1 degradation. Finally, we demonstrate that CARM1 expression in podocytes was diminished in rats with streptozotocin-induced diabetes compared to vehicle-treated rats. Together, our data provide evidence that ubiquitination-dependent CARM1 degradation in podocytes in diabetes promotes podocyte apoptosis via Notch1 activation. Strategies to preserve CARM1 expression or reduce the enzymatic activity of a ubiquitin ligase specific for CARM1 could be used to prevent podocyte loss in diabetic nephropathy.