title: Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility.
abstract: Carbonic anhydrase 2 regulates acid-base homeostasis, and recent findings have indicated a correlation between cellular control of acid-base status and the innate defense of the kidney. Mice deficient in carbonic anhydrase 2 (Car2(-/-) mice) have metabolic acidosis, impaired urine acidification, and are deficient in normal intercalated cells. The objective of the present study was to evaluate the biological consequences of carbonic anhydrase 2 deficiency in a murine model of pyelonephritis. Infection susceptibility and transcription of bacterial response components in Car2(-/-) mice were compared with wild-type littermate controls. Car2(-/-) mice had increased kidney bacterial burdens along with decreased renal bacterial clearance after inoculation compared with wild-type mice. Standardization of the urine pH and serum HCO(3)(-) levels did not substantially alter kidney infection susceptibility between wild-type and Car2(-/-) mice; thus, factors other than acid-base status are responsible. Car2(-/-) mice had significantly increased neutrophil-gelatinase-associated lipocalin mRNA and protein and expression at baseline and a marked decreased ability to upregulate key bacterial response genes during pyelonephritis. Our findings provide in vivo evidence that supports a role for carbonic anhydrase 2 and intercalated cells in promoting renal bacterial clearance. Decreased carbonic anhydrase expression results in increased antimicrobial peptide production by cells other than renal intercalated cells, which is not sufficient to prevent infection after a bacterial challenge.
authors.affiliation: Division of Nephrology, Le Bonheur Children's Hospital, Memphis, Tennessee;
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.affiliation: Division of Nephrology, Le Bonheur Children's Hospital, Memphis, Tennessee; Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Vijay
authors.initials: V
authors.lastname: Saxena
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Evan
authors.initials: E
authors.lastname: Barr-Beare
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Weisi
authors.initials: W
authors.lastname: Flemming
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Robert
authors.initials: R
authors.lastname: Easterling
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Division of Nephrology, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio;
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.affiliation: Department of Pediatrics, The University of Rochester, Rochester, New York.
authors.forename: George J
authors.initials: GJ
authors.lastname: Schwartz
authors.affiliation: Center for Clinical and Translational Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Division of Nephrology, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio; Schwaderer.5@osu.edu.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Schwaderer
mesh_terms: D000141:Acidosis, Renal Tubular / Q000150:complications*; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000172:deficiency*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010022:Osteopetrosis / Q000150:complications*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011704:Pyelonephritis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D056806:Urea Cycle Disorders, Inborn / Q000150:complications*; D014556:Urine
chemical_list: D001639:Bicarbonates; D054834:Lipocalins; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases
keywords: acid-base; inflammation; intercalated cells; urinary tract infection