Kim Dongil, Lim Seulki, Park Minjung, Choi Joohee, Kim Jongchoon, Han Hojae, Yoon Kyungchul, Kim Kwonseop, Lim Jaehyang, Park Soohyun
College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
Department of Verterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Cell Signal. 2014 Sep;26(9):1774-82. doi: 10.1016/j.cellsig.2014.04.008. Epub 2014 Apr 12.
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.
高血糖诱导的足细胞凋亡被认为是糖尿病肾病发生发展的关键因素。最近的研究表明Notch信号传导与足细胞凋亡有关；然而，其调控机制尚未完全明确。在本研究中，我们发现高糖处理可增加大鼠足细胞中Notch1和Jagged-1的表达、Hes的转录活性以及足细胞凋亡，并降低共激活因子相关精氨酸甲基转移酶1（CARM1）的表达。瞬时转染CARM1可逆转高糖诱导的Notch1表达、Hes的转录活性以及足细胞凋亡。此外，使用小干扰RNA沉默CARM1可增加Notch1表达、Hes的转录活性以及足细胞凋亡。然而，CARM1的Glu(266)介导的酶活性对于Notch信号激活和足细胞凋亡并非必需。在此，我们证明AMP激活的蛋白激酶α（AMPKα）和大麻素受体1（CB1R）受CARM1调控，且高糖诱导的足细胞凋亡由CARM1-AMPKα-Notch1-CB1R信号轴介导。我们还表明高糖诱导的CARM1下调是由于泛素化依赖性的CARM1降解。最后，我们证明与用赋形剂处理的大鼠相比，链脲佐菌素诱导的糖尿病大鼠足细胞中CARM1的表达降低。总之，我们的数据表明糖尿病中足细胞内泛素化依赖性的CARM1降解通过Notch1激活促进足细胞凋亡。维持CARM1表达或降低特异性针对CARM1的泛素连接酶的酶活性的策略可用于预防糖尿病肾病中的足细胞丢失。
