title: Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli.
abstract: The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc-/-) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc-/- mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc-/- mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion.
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Dounia
authors: D
authors: Houamel
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Nicolas
authors: N
authors: Ducrot
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France; AP-HP, French Center for Porphyrias, Louis Mourier Hospital, Colombes, France;
authors: Thibaud
authors: T
authors: Lefebvre
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Raed
authors: R
authors: Daher
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Boualem
authors: B
authors: Moulouel
authors: The National Centre for Scientific Research (CNRS), UMR 8601, Descartes University, Paris, France;
authors: Marie-Agnes
authors: MA
authors: Sari
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France;
authors: Philippe
authors: P
authors: Letteron
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Said
authors: S
authors: Lyoumi
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Sarah
authors: S
authors: Millot
authors: Paris Diderot University, Sorbonne Paris Cité, Paris, France; INSERM U1137, Infection Antimicrobials Modelling Evolution (IAME) Laboratory, Paris, France; and.
authors: Jerome
authors: J
authors: Tourret
authors: Paris Diderot University, Sorbonne Paris Cité, Paris, France; INSERM U1137, Infection Antimicrobials Modelling Evolution (IAME) Laboratory, Paris, France; and.
authors: Odile
authors: O
authors: Bouvet
authors: Laboratory of Excellence, GR-Ex, Paris, France; INSERM U1016, Cochin Institute, Descartes University, Paris, France.
authors: Sophie
authors: S
authors: Vaulont
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France;
authors: Alain
authors: A
authors: Vandewalle
authors: Paris Diderot University, Sorbonne Paris Cité, Paris, France; INSERM U1137, Infection Antimicrobials Modelling Evolution (IAME) Laboratory, Paris, France; and.
authors: Erick
authors: E
authors: Denamur
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France; AP-HP, French Center for Porphyrias, Louis Mourier Hospital, Colombes, France;
authors: Hervé
authors: H
authors: Puy
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France;
authors: Carole
authors: C
authors: Beaumont
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France; AP-HP, French Center for Porphyrias, Louis Mourier Hospital, Colombes, France;
authors: Laurent
authors: L
authors: Gouya
authors: National Institute of Health and Medical Research (INSERM) U1149, Research Centre on inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; Laboratory of Excellence, GR-Ex, Paris, France; zoubida.karim@inserm.fr.
authors: Zoubida
authors: Z
authors: Karim
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D058491:Bacterial Load / Q000235:genetics; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology; D005260:Female; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D007679:Kidney Medulla / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009393:Nephritis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014552:Urinary Tract Infections / Q000378:metabolism* / Q000382:microbiology
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D064451:Hepcidins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; C494087:Stat3 protein, mouse; D007501:Iron
keywords: cell and transport physiology; cell signaling; kidney disease; pyelonephritis; renal epithelial cell; renal protection