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Abstract: TH-PO182

Insulin Resistance Deregulates Immune Functions in the Collecting Duct That May Increase Urinary Tract Infection Risk

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Schwartz, Laura, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Tyagi, Vidhi, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Bender, Kristin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Type 2 diabetes affects 10% of the population. Among comorbidities linked to diabetes is increased urinary tract infection (UTI) risk. The factors that increase UTI susceptibility remain unknown. Previously, we showed insulin resistance and disrupted insulin receptor signaling in kidney collecting ducts (CD) and intercalated cells (IC) increases UTI risk. Here, we assess how adipose-derived cytokines impact CD insulin sensitivity, uropathogenic E.coli (UPEC) susceptibility, and UTI defenses in vitro. To validate these effects in vivo, we profile the transcriptomes of IC and principal cells (PC) from obese, insulin resistant male and female mice.

Methods

To induce insulin resistance (IR) in vitro, mouse and human CD cells were cultured with adipokines or in hypoxic conditions followed by a 1-hour treatment with insulin. Western blotting evaluated insulin signaling and UTI defense targets. To determine if IR effects UTI susceptibility, UPEC attachment and invasion assays assessed were performed on CD cells cultured in IR conditions. To assess the effects of IR on CD immune defenses in vivo, we placed female and male C57BL/6 mice on a high-fat diet (HFD) or low-fat diet (LFD) for 8 weeks. We then enriched IC and PC populations from HFD and LFD mice using fluorescence activated cell sorting and performed RNA-seq analysis.

Results

TNFa, IL-1b and culturing CD cells in hypoxic conditions increased IR in vitro, as shown by decreased insulin receptor and PI3K/AKT activation following insulin treatment. Culturing cells in these conditions deregulated immune targets, including NFkB, MAP kinase, and integrated stress responses. They also resulted in greater UPEC attachment to and invasion of CD cells. Gene expression profiles between HFD- and LFD-fed murine IC and PC populations also revealed altered expression in innate immune pathways, including NFkB signaling and the integrated stress response.

Conclusion

These results suggest insulin resistance may directly impact immune mechanisms that shield the kidneys from UPEC. In part, this may be due to the production of adipose-derived circulating cytokines that dysregulate immune mechanisms like NFkB signaling and the integrated stress response. A deeper understanding of these mechanisms may provide insight into why people with insulin resistance or diabetes have increased UTI susceptibility.

Funding

  • NIDDK Support