title: Activation of endogenous anti-inflammatory mediator cyclic AMP attenuates acute pyelonephritis in mice induced by uropathogenic Escherichia coli.
abstract: The pathogenesis of pyelonephritis caused by uropathogenic Escherichia coli (UPEC) is not well understood. Here, we show that besides UPEC virulence, the severity of the host innate immune response and invasion of renal epithelial cells are important pathogenic factors. Activation of endogenous anti-inflammatory mediator cAMP significantly attenuated acute pyelonephritis in mice induced by UPEC. Administration of forskolin (a potent elevator of intracellular cAMP) reduced kidney infection (ie, bacterial load, tissue destruction); this was associated with attenuated local inflammation, as evidenced by the reduction of renal production of proinflammatory mediators, renal infiltration of inflammatory cells, and renal myeloperoxidase activity. In primary cell culture systems, forskolin not only down-regulated UPEC-stimulated production of proinflammatory mediators by renal tubular epithelial cells and inflammatory cells (eg, monocyte/macrophages) but also reduced bacterial internalization by renal tubular epithelial cells. Our findings clearly indicate that activation of endogenous anti-inflammatory mediator cAMP is beneficial for controlling UPEC-mediated acute pyelonephritis in mice. The beneficial effect can be explained at least in part by limiting excessive inflammatory responses through acting on both renal tubular epithelial cells and inflammatory cells and by inhibiting bacteria invasion of renal tubular epithelial cells.
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China. Electronic address: ke.li@mail.xjtu.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Cai
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Bao-Song
authors.initials: BS
authors.lastname: Gui
authors.affiliation: Research Institute of Atherosclerotic Disease, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: En-Qi
authors.initials: EQ
authors.lastname: Liu
authors.affiliation: Department of General Surgery in Cadre's Ward, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Zong-Fang
authors.initials: ZF
authors.lastname: Li
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, London, United Kingdom. Electronic address: wuding.zhou@kcl.ac.uk.
authors.forename: Wuding
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007686:Kidney Tubules, Distal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011704:Pyelonephritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015290:Second Messenger Systems; D014552:Urinary Tract Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D056689:Uropathogenic Escherichia coli / Q000276:immunology / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP