title: Cyclin-dependent kinase 5 contributes to endoplasmic reticulum stress induced podocyte apoptosis via promoting MEKK1 phosphorylation at Ser280 in diabetic nephropathy.
abstract: Endoplasmic reticulum (ER) stress has been reported to be associated with podocyte apoptosis in diabetic nephropathy, but the mechanism of ER signaling in podocyte apoptosis hasn't been fully understood. Our previous studies have demonstrated that Cyclin-dependent kinase 5 (Cdk5) was associated with podocyte apoptosis in diabetic nephropathy. The present study was designed to examine whether and how Cdk5 activity plays a role in ER stress induced podocyte apoptosis in diabetic nephropathy. The results showed that along with induction of Cdk5 and apoptosis, GRP78 and its two sensors as well as CHOP and cleaved caspase-12 were induced in high glucose treated podocytes. These responses were attenuated by treated salubrinal. The ER stress inducer, tunicamycin, also up-regulated the kinase activity and protein expression of Cdk5 in podocytes accompanied with the increasing of GRP78. On the other hand, Cdk5 phosphorylates MEKK1 at Ser280 in tunicamycin treated podocytes, and together, they increase the JNK phosphorylation. Moreover, disruption of this pathway can decrease the podocyte apoptosis induced by tunicamycin. Therefore, our study proved that Cdk5 may play an important role in ER stress induced podocyte apoptosis through MEKK1/JNK pathway in diabetic nephropathy.
authors.affiliation: Department of Diagnostics, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Shuanggang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Shengyang
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: weiliu0209@hebmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D050199:Podocytes / Q000473:pathology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; C496827:salubrinal; D014415:Tunicamycin; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5; D048728:MAP Kinase Kinase Kinase 1; D013890:Thiourea; D005947:Glucose
keywords: Apoptosis; Cyclin-dependent kinase 5; Diabetic nephropathy; Endoplasmic reticulum stress; Podocyte