title: Inflammation drives renal scarring in experimental pyelonephritis.
abstract: Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis.
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Birong
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Neurology, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Babitha
authors.initials: B
authors.lastname: Haridas
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Jackson
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cortado
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mayne
authors.affiliation: College of Veterinary Medicine and Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kohnken
authors.affiliation: GEMPath, Inc., Longmont, Colorado.
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Department of Anatomy, The Ohio State University College of Allied Health Sciences, Columbus, Ohio.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: McHugh
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Division of Nephrology, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Schwaderer
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Division of Nephrology, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: John David
authors.initials: JD
authors.lastname: Spencer
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Division of Urology, Department of Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Ching
authors.affiliation: Children's Research Foundation Institute, Le Bonheur Children's Hospital, Memphis, Tennessee; and.
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.affiliation: Division of Urology, Department of Surgery, The Ohio State University, Columbus, Ohio.|Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Justice
authors.affiliation: Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Santiago
authors.initials: S
authors.lastname: Partida-Sanchez
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Brian.becknell2@nationwidechildrens.org.|Division of Nephrology, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Brian
authors.identifier: 0000-0002-2750-4415
authors.initials: B
authors.lastname: Becknell
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000378:metabolism*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000302:isolation & purification*; D005260:Female; D005355:Fibrosis / Q000276:immunology / Q000382:microbiology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D007668:Kidney / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009395:Nephritis, Interstitial / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011704:Pyelonephritis / Q000276:immunology / Q000382:microbiology*; D015427:Reperfusion Injury / Q000382:microbiology / Q000473:pathology; D014718:Vesico-Ureteral Reflux / Q000276:immunology* / Q000382:microbiology
keywords: fibrosis; inflammation; mucosal injury; pyelonephritis; urinary tract infection; vesicoureteral reflux