title: Ubiquitination-dependent CARM1 degradation facilitates Notch1-mediated podocyte apoptosis in diabetic nephropathy.
abstract: 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.
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Dongil
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Minjung
authors.initials: M
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Choi
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Jongchoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Verterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hojae
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Kyungchul
authors.initials: K
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Research Institute for Drug Development, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Ewha Womans University School of Medicine, Seoul, Republic of Korea. Electronic address: jlim19@ewha.ac.kr.
authors.forename: Jaehyang
authors.initials: J
authors.lastname: Lim
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: parksh@chonnam.ac.kr.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000633:toxicity; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D051881:Receptor, Notch1; D025801:Ubiquitin; D013311:Streptozocin; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat; D053148:Caspase 3; D005947:Glucose
keywords: CARM1; Notch1; PRMT; Podocyte apoposis; Protein arginine methyltransferase; Ubiquitination