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Insulin receptor orchestrates kidney antibacterial defenses.
Schwartz, Laura; Simoni, Aaron; Yan, Pearlly; Salamon, Kristin; Turkoglu, Altan; Vasquez Martinez, Gabriela; Zepeda-Orozco, Diana; Eichler, Tad; Wang, Xin; Spencer, John David.
Affiliation
  • Schwartz L; The Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205.
  • Simoni A; Division of Nephrology and Hypertension, Department of Pediatrics, Nationwide Children's, Columbus, OH 43205.
  • Yan P; The Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205.
  • Salamon K; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210.
  • Turkoglu A; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210.
  • Vasquez Martinez G; The Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205.
  • Zepeda-Orozco D; Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210.
  • Eichler T; The Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205.
  • Wang X; The Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205.
  • Spencer JD; Division of Nephrology and Hypertension, Department of Pediatrics, Nationwide Children's, Columbus, OH 43205.
Proc Natl Acad Sci U S A ; 121(29): e2400666121, 2024 Jul 16.
Article in En | MEDLINE | ID: mdl-38976738
ABSTRACT
Urinary tract infection (UTI) commonly afflicts people with diabetes. This augmented infection risk is partly due to deregulated insulin receptor (IR) signaling in the kidney collecting duct. The collecting duct is composed of intercalated cells (ICs) and principal cells (PCs). Evidence suggests that ICs contribute to UTI defenses. Here, we interrogate how IR deletion in ICs impacts antibacterial defenses against uropathogenic Escherichia coli. We also explore how IR deletion affects immune responses in neighboring PCs with intact IR expression. To accomplish this objective, we profile the transcriptomes of IC and PC populations enriched from kidneys of wild-type and IC-specific IR knock-out mice that have increased UTI susceptibility. Transcriptomic analysis demonstrates that IR deletion suppresses IC-integrated stress responses and innate immune defenses. To define how IR shapes these immune defenses, we employ murine and human kidney cultures. When challenged with bacteria, murine ICs and human kidney cells with deregulated IR signaling cannot engage central components of the integrated stress response-including activating transcriptional factor 4 (ATF4). Silencing ATF4 impairs NFkB activation and promotes infection. In turn, NFkB silencing augments infection and suppresses antimicrobial peptide expression. In diabetic mice and people with diabetes, collecting duct cells show reduced IR expression, impaired integrated stress response engagement, and compromised immunity. Collectively, these translational data illustrate how IR orchestrates collecting duct antibacterial responses and the communication between ICs and PCs.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Urinary Tract Infections / Receptor, Insulin / Mice, Knockout / Uropathogenic Escherichia coli Limits: Animals / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Urinary Tract Infections / Receptor, Insulin / Mice, Knockout / Uropathogenic Escherichia coli Limits: Animals / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Country of publication: