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Abstract: FR-PO372

Obesity Augments Urinary Tract Infection Susceptibility by Activating Focal Adhesion Kinase in Kidney Intercalated Cells

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Schwartz, Laura, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Bender, Kristin, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Wang, Xin, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Obesity affects a third of the global population. Among the comorbidities linked to obesity is increased urinary tract infection (UTI) and pyelonephritis risk. The obesity mediated factors that increase UTI risk are unknown. In this study, we assess the impact of diet-induced obesity on UTI susceptibility using male and female mice. Because recent data show intercalated cells (IC) in the kidney have a key role in protecting against UTI and pyelonephritis, we also assess how diet-induced obesity effects murine IC gene expression and antibacterial defenses.

Methods

C57/BL6 male and female mice were fed a high fat diet (HFD; 60 kcal% fat) or standard diet (SD; 10% kcal fat) for 8-12 weeks. Mice were subjected to experimental UTI and infected with UPEC. UPEC burden was quantified 24 hours after infection. ICs from SD and HFD fed mouse kidneys were enriched using FACS and subjected to RNAseq. Differentially expressed genes were used to generate lists of enriched pathways and ontologies. Western blot confirmed pathway suppression or activation. To test how these pathways impact UTI outcomes, ICs were cultured to confluency, treated with target inhibitors, and challenged with UPEC.

Results

Male and female mice fed a HFD showed a 30% increase in body weight, reduced insulin sensitivity measured by glucose tolerance testing, and 10-100-fold greater UPEC burden following UTI. Changes in gene expression in ICs from HFD and SD mice diverged depending on sex. Activation of focal adhesion kinase (FAK) was consistent between sexes when comparing HFD and SD ICs. Western blot confirmed increased FAK signaling in HFD kidneys, as well as increased NFkB, a downstream FAK target. When cultured ICs were treated with the FAK inhibitor PF-573228 and challenged with UPEC, bacterial invasion was abolished.

Conclusion

These results suggest that diet-induced obesity leads to increased UTI susceptibility by activating FAK signaling in ICs. Future studies will investigate the factors regulating FAK as targets for reducing UTI risk.

Funding

  • NIDDK Support