title: AMPK-mediated downregulation of connexin43 and premature senescence of mesangial cells under high-glucose conditions.
abstract: Diabetic nephropathy is associated with premature senescence. Our previous study showed that glomerular mesangial cells (GMCs) appeared to take on senescent phenotypes under high-glucose conditions in conjunction with the downregulation of connexin43 (Cx43). In this study, we investigated whether AMPK-mediated Cx43 expression and premature senescence in diabetic nephropathy are associated with mTOR activation. From in vivo and in vitro studies, we found decreased expression of Cx43 and p-AMPK but increased expression of p21 both in the glomeruli of diabetic nephropathy and in primary GMCs cultured in high glucose. Activating AMPK or inhibiting mTOR prevented the downregulation of Cx43 and reversed GMC senescence. Dominant-negative AMPK expression both reduced Cx43 expression and induced GMC senescence. Furthermore, AMPK regulated Cx43 expression and GMC senescence mainly through the inhibition of mTOR, although other pathways cannot be ruled out. This study demonstrated that AMPK signaling pathways play an important role in the regulation of the Cx43 expression that accompanies GMC senescence under high-glucose conditions.
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Guo
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China; The Third Hospital of Hebei Medical University, China.
authors.forename: Jing-Chao
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China. Electronic address: caiguangyan@sina.com.
authors.forename: Guang-Yan
authors.initials: GY
authors.lastname: Cai
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Shao-Yuan
authors.initials: SY
authors.lastname: Cui
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China. Electronic address: xmchen301@126.com.
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D018031:Connexin 43 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism; D015536:Down-Regulation; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism / Q000502:physiology*; D008687:Metformin / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013549:Sweetening Agents / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D018031:Connexin 43; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007004:Hypoglycemic Agents; D013549:Sweetening Agents; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D020123:Sirolimus
keywords: AMPK; Connexin43; Diabetic nephropathy; Mesangial cell senescence; mTOR