Role of gap junction-mediated intercellular communication on schaemia/reperfusion renal injury

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591187
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: University of Yamanashi
• Principal Investigator: YAO Jian 山梨大学, 医学工学総合研究部, 准教授 (50303128)
• Co-Investigator(Kenkyū-buntansha): KITAMURA Masanori 山梨大学, 医学工学総合研究部, 教授 (90333062)
• Project Period (FY): 2011 – 2013
• Keywords: 病理学 / 腎臓 / 虚血 / 細胞死 / ギャップ結合 / 酸化ストレス / AMPK / ATP

Research Abstract

Connexin-forming channels regulates cell survival with little information available regarding its mechanisms. Using a ischemic renal injury model, we explored the potential mechanisms of Cx43-forming channels on renal cell survival. Our results showed that Cx43 influenced cell susceptibility to ischemic renal injury. Cells with higher level of Cx43 were more vulnerable to ischemic oxidative injury. On the contrary, cells with no or lower level of Cx43 were resistant. Further analysis revealed that oxidative stimuli activated Cx43 hemichannels, leading to extracellular loss of ATP. The released ATP, in turn, suppressed AMPK activation through purinergistic receptor-mediated activation of AKT and mTOR. Suppression of hemichannels enhanced AMPK activation, thus protecting cells from oxidative injury. Our study indicates that Cx43 hemichannels determines cell susceptibility to oxidative injury. Targeting Cx43 could be developed for prevention and treatment of ischemic renal injury.

Research Products

• [Journal Article] Suppression of cell membrane permeability by suramin : involvement of its inhibitory actions on connexin 43 hemichannels (2014)
  • Author(s): Chi Y, Gao K, Zhang H, Takeda M and Yao J
  • Journal Title: Br J Pharmacol
  • DOI: 10.1111/bph.12693
  • Peer Reviewed
• [Journal Article] Purinergic control of AMPK activation by ATP released through connexin 43 hemichannels : pivotal roles in hemichannel-mediated cell injury (2014)
  • Author(s): Chi Y, Gao K, Li K, Nakajima S, Kira S, Takeda M and Yao J
  • Journal Title: J Cell Sci Volume: Vol.1 Pages: 1487-1499
  • DOI: 10.1242/jcs.139089
  • Peer Reviewed
• [Journal Article] 5'-AMP-Activated protein kinase attenuates adriamycin-induced oxidative podocyte injury through thioredoxin-mediated suppression of the apoptosis signal-regulating kinase 1-P38 signaling pathway (2014)
  • Author(s): Gao K, Chi Y, Sun W, Takeda M and Yao J
  • Journal Title: Mol Pharmacol Volume: Vol.85, No.3 Pages: 460-471
  • DOI: 10.1124/mol.113.089458
  • Peer Reviewed
• [Journal Article] Glomerular expression of connexin 40 and connexin 43 in rat experimental glomerulonephritis (2013)
  • Author(s): Morioka T, Okada S, Nameta M, Kamal F, Yanakieva-Georgieva NT, Yao J, Sato A, Piao H and Oite T
  • Journal Title: Clin Exp. Nephrol Volume: Vol.17, No.2 Pages: 191-204
  • DOI: 10.1007/s10157-012-0687-2
  • Peer Reviewed
• [Journal Article] Eviprostat activates cAMP signaling pathway and suppresses bladder smooth muscle cell proliferation (2013)
  • Author(s): Li K, Yao J, Chi Y, Sawada N, Araki I, Kitamura M and Takeda M
  • Journal Title: Int J Mol Sci Volume: Vol.14, No.6 Pages: 12107-12122
  • DOI: 10.3390/ijms140612107
  • Peer Reviewed
• [Journal Article] Connexin43 hemichannel-mediated regulation of connexin43 (2013)
  • Author(s): Li K, Chi Y, Gao K, Yan Q, Matsue H, Takeda M, Kitamura M and Yao J
  • Journal Title: PloS one Volume: Vol.8, No.2 Pages: e58057
  • DOI: 10.1371/journal.pone.0058057
  • Peer Reviewed
• [Journal Article] NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury (2012)
  • Author(s): Yan Q, Gao K, Chi Y, Li K, Zhu Y, Wan Y, Sun W, Matsue H, Kitamura M and Yao J
  • Journal Title: Free Radic Biol Med Volume: Vol.53, No.6 Pages: 1286-97
  • DOI: 10.1016/j.freeradbiomed.2012.07.012
  • Peer Reviewed
• [Journal Article] β-catenin signaling contributes to PDGF-elicited bladder smooth muscle cell contraction through upregulation of Cx43 expression (2012)
  • Author(s): Li K, Yao J, Sawada N, Kitamura M, Andersson KE and Takeda M
  • Journal Title: J Urol Volume: Vol.188, No.1 Pages: 307-315
  • DOI: 10.1016/j.juro.2012.02.2556
  • Peer Reviewed
• [Journal Article] Reciprocal regulation between proinflammatory cytokine-induced inducible NO synthase and connexin43 in bladder smooth muscle cells (2011)
  • Author(s): Li K, Yao J, Shi L, Sawada N, Chi Y, Yan Q, Matsue H, Kitamura M and Takeda M
  • Journal Title: J Biol Chem Volume: Vol.286, No.48 Pages: 41552-41562
  • DOI: 10.1074/jbc.M111.274449
  • Peer Reviewed
• [Journal Article] Nonsteroidal anti-inflammatory drug flufenamicacid is a potent activator of AMPK (2011)
  • Author(s): Chi Y, Li K, Yan Q, Koizumi S, Shi L, Takahashi S, Zhu Y, Matsue H, Takeda M, Kitamura M and Yao J
  • Journal Title: J Pharmacol Exp Ther Volume: Vol.339, No.1 Pages: 257-66
  • DOI: 10.1124/jpet.111.183020
  • Peer Reviewed
• [Presentation] Activation of AMPK Protects podocytes from Adriamycin-elicited Injury (2013)
  • Author(s): Gao K, Sun W, Chi Y, Kitamura M, and Yao J
  • Organizer: International Society of Nephrology (ISN) World Congress of Nephrology 2013
  • Place of Presentation: Hong Kong
  • Year and Date: 20130531-0604
• [Presentation] Purinergic control of AMPK activation by ATP released through connexin43 hemichannels : pivotal roles in hemichannel-mediated disassembly of tight junction and cell injury (2013)
  • Author(s): Yao J
  • Organizer: International Gap Junction Conference
  • Place of Presentation: Charleston, South Carolina
  • Year and Date: 2013-07-15
• [Presentation] Connexin43 hemichannel-mediated release of ATP suppresses AMPK activation in renal tubular epithelial cells (2012)
  • Author(s): Chi Y, Gao K, Kato H, Nakajima S, Kitamura M, and Yao J
  • Organizer: 45^<th> Annual Meeting of American Society of Nephrology
  • Place of Presentation: San Diego
  • Year and Date: 2012-11-02
• [Presentation] beta-catenin signaling contributes to PDGF-elicited bladder smooth muscle cell contraction through upregulation of Cx43 expression (2012)
  • Author(s): Li K, Yao J, Sawada N, Miyamoto T, Kitamura M, Takeda M
  • Organizer: 2012 Annual Meeting of American Urology Association
  • Place of Presentation: Atlanta
  • Year and Date: 2012-05-19
• [Presentation] Suppression of inflammatory cytokines-triggered NFB activation and iNOS expression in renal tubular cells by gap junction inhibitor flufenamic acid : a critical involvement of AMPK (2011)
  • Author(s): Chi Y, Yan QJ, Zhu Y, Kitamura M, and Yao J
  • Organizer: 44th Annual Meeting of The American Society of Nephrology
  • Place of Presentation: Pennsylvania, Philadelphia
  • Year and Date: 20111108-13
• [Presentation] Connexin43 contributes to puromycin-elicited podocyte injury (2011)
  • Author(s): Yan QJ Chi Y, Zhu Y, Kitamura M, and Yao J
  • Organizer: 44th Annual Meeting of The American Society of Nephrology
  • Place of Presentation: Pennsylvania, Philadelphia
  • Year and Date: 20111108-13
• [Presentation] Dysfunction of gap junctions stimulates COX-2 expression in juxtaglomerular renin-secreting cells (2011)
  • Author(s): Yao J, Zhu Y, and Kitamura M
  • Organizer: 44th Annual Meeting of The American Society of Nephrology
  • Place of Presentation: Pennsylvania, Philadelphia
  • Year and Date: 20111108-13
• [Presentation] NF-κB/iNOS/cAMP signaling cascade mediates inflammatory cytokines-induced upregulation of connexin43 expression and function in urinary tract infection (2011)
  • Author(s): Li K, Yao J, Sawada N, Nakagomi H, Miyamoto T, Kira S, Kobayashi H, Tsuchida T, Kitamura M and Takeda M
  • Organizer: The 2011 American Urological Association Annual Meeting
  • Place of Presentation: Washington, D.C.
  • Year and Date: 20110514-19
• [Presentation] Roles of gap junctional intercellular communication in renal cell injury (2011)
  • Author(s): Yao J
  • Organizer: 国際中西医結合腎臓病学術大会
  • Place of Presentation: 中国北京
  • Year and Date: 2011-11-25