title: Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract.
abstract: Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. Because the impact of diabetes on RNase 7 expression and function are unknown, we investigated the effects of insulin on RNase 7 using human urine specimens. The urinary RNase 7 concentrations were measured in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared with controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, the mechanisms by which insulin stimulates RNase 7 synthesis were next explored. Insulin induced RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, uropathogenic E. coli suppressed PI3K/AKT activity and RNase 7 production. Thus, insulin and PI3K/AKT signaling are essential for RNase 7 expression and increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. Our data may provide unique insight into novel urinary tract infection therapeutic strategies in at-risk populations.
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Tad E
authors.initials: TE
authors.lastname: Eichler
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA; Division of Nephrology, Department of Pediatrics, Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA; University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Easterling
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA; Division of Nephrology, Department of Pediatrics, Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ingraham
authors.affiliation: Division of Emergency Medicine, Department of Pediatrics, Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA; Division of Nephrology, Department of Pediatrics, Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Schwaderer
authors.affiliation: Innate Immunity Translational Research Center, Department of Pediatrics, Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Birong
authors.initials: B
authors.lastname: Li
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA.
authors.forename: Jackie
authors.initials: J
authors.lastname: Metheny
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA; Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Center for Clinical and Translational Research, Department of Pediatrics, The Research Institute at Nationwide Children's, Columbus, Ohio, USA; Division of Nephrology, Department of Pediatrics, Nationwide Children's, Columbus, Ohio, USA. Electronic address: John.Spencer@nationwidechildrens.org.
authors.forename: John David
authors.initials: JD
authors.lastname: Spencer
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000652:urine; D004926:Escherichia coli / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000652:urine; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism* / Q000652:urine; D015398:Signal Transduction; D014551:Urinary Tract / Q000378:metabolism* / Q000382:microbiology; D014552:Urinary Tract Infections / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000652:urine
chemical_list: D015703:Antigens, CD; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D012260:Ribonucleases; C435941:INSR protein, human; C470000:Ribonuclease 7
keywords: cell signaling; diabetes; pyelonephritis; urology