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Abstract: SA-PO250

Histone Deacetylase Inhibitors Enhance the Urinary Tract's Immune Response in Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Simoni, Aaron A., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Schwartz, Laura, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Bochter, M. Skye N., 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

People with diabetes mellitus (DM) have an increased risk for developing urinary tract infection (UTI). With UTI, people with DM are more likely to experience acute kidney injury and develop chronic kidney disease. Epigenetic mechanisms such as histone and protein acetylation have emerged as factors contributing to DM and may impact UTI risk. Recently, a class of drugs called histone deacetylase inhibitors (HDACi) have been shown to improve glucose sensitivity as well as decrease infection risk. To investigate the role of HDACi on UTI antibacterial defenses, we treated diabetic mice with MS-275, a class I HDACi.

Methods

Type 2 DM db/db mice, which have increased UTI susceptibility, were treated with 10mg/kg intraperitoneal (i.p.) MS-275 every 48 hours for a total of 8 doses. Weight, blood glucose, urine glucose, and serum insulin concentrations were measured after MS-275 or vehicle treatment. We also assessed insulin sensitivity by performing a glucose tolerance test in which mice were fasted for 6 hours and given i.p. glucose (1g/kg) prior to obtaining serial blood glucose measurements. Quantitative real-time PCR (qRT-PCR) was used to quantify innate immune genes that prevent UTI, including urothelial barrier genes that prevent bacterial invasion and antimicrobial peptides (AMP) which kill invading pathogens.

Results

After 4 doses of MS-275, serum glucose and insulin concentrations in diabetic mice normalized and decreased 7-fold. MS-275 treated mice also had significantly lower glucosuria, showing an 8-fold reduction compared to vehicle treated mice. MS-275 treatment improved glucose tolerance while vehicle treated mice showed minimal glucose clearance. qRT-PCR showed suppressed bladder HDAC expression with MS-275 treatment. Importantly, we observed an induction of bladder urothelial barrier genes (Tjp1, Cldn2, Cldn4, Upk1a, and Upk2) and AMPs (Camp, Defb1, Lcn2, Rnase4, Slpi) in MS-275 treated mice compared to vehicle.

Conclusion

These results suggest that histone acetylation status may play a role in DM-mediated UTI defense. By increasing bladder barrier strength and AMP production using MS-275, the kidneys may be shielded from the deleterious effects of DM and UTI. Further studies are needed to assess the effectiveness of using MS-275 in individuals with DM to reduce UTI susceptibility and protect the kidneys.

Funding

  • NIDDK Support