The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children’s, Columbus, OH 43205, USA
Kristin Salamon
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Aaron Simoni
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Tad Eichler
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Ashley R. Jackson
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children’s, Columbus, OH 43205, USA
Matthew Murtha
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Brian Becknell
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children’s, Columbus, OH 43205, USA
Andrew Kauffman
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Tulane University, New Orleans, LA 70118, USA
Sarah Linn-Peirano
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, OH 43210, USA
Natalie Holdsworth
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701, USA
Vidhi Tyagi
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Hancong Tang
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Steve Rust
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Hanna Cortado
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA
Irina Zabbarova
Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Anthony Kanai
Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
John David Spencer
The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children’s, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children’s, Columbus, OH 43205, USA; Corresponding author
Summary: Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling to show that insulin receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report that diabetic mice have suppressed IR expression and are more susceptible to UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic IR inhibition increases UPEC susceptibility, while IR activation reduces UTIs. Localized IR deletion in bladder urothelium promotes UTI by increasing barrier permeability and suppressing antimicrobial peptides. Mechanistically, IR deletion reduces nuclear factor κB (NF-κB)-dependent programming that co-regulates urothelial tight junction integrity and antimicrobial peptides. Exfoliated urothelial cells or urine samples from diabetic youths show suppressed expression of IR, barrier genes, and antimicrobial peptides. These observations demonstrate that urothelial insulin signaling has a role in UTI prevention and link IR to urothelial barrier maintenance and antimicrobial peptide expression.
