Abstract: TH-PO276

Transcriptional Response of the Intercalated Cells to UTI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Xu, Katherine, Columbia University Medical Center, New York, New York, United States
  • Shen, Tian, Columbia University, New York, New York, United States
  • Barasch, Jonathan M., Columbia Presbyterian, New York, New York, United States
Background

Urinary tract infections (UTI) are among the most prevalent bacterial infections acquired in US hospitals, and complications can lead to urinary obstruction, bacteremia, urosepsis. We found that uropathogenic E. coli (UPEC) require iron for infection: loading with iron dextran resulted in significantly more urinary colony forming units (CFUs) than mice without prior iron loading; conversely iron-deficient mice (4 weeks of iron-deficient chow) demonstrated markedly reduced CFUs compared with iron-sufficient mice (regular chow). The form of iron was also important, heme iron was stoichometrically more powerful as a stimulant than ferric iron. These data raise the question as to how the nephron controls luminal and interstitial iron content and how bacteria disrupt these homeostatic mechanisms.

Methods

To study the process by which UPECs interact with the kidney to obtain iron, we generated a novel cell- and time-specific in-vivo RNA-labeling technique to purify specific RNA species from the intercalated cells (IC) in a UTI model.

Results

We analyzed newly synthesized RNA. RNA-sequencing demonstrated a robust transcriptional response of ICs 12 hours after UTI (95% of induced genes). Many of these upregulated genes were involved in iron and heme transport and storage, such as heme-responsive gene 1 (Hrg1), heme oxygenase (Ho1), and ferritin heavy chain (Fth1), suggesting that heme metabolism is a critical component of UTI and a mechanism of immune defense. After 24hrs these transcripts were no longer expressed.

Conclusion

A thorough investigation of iron transporters throughout the nephron revealed megalin in the proximal tubule, TfR1 in the thick limb of Henle, DMT1 in the distal convoluted tubule but remarkably none of these proteins were found in the collecting duct. In summary, we suggest that the nephron is able to recover iron using many different transport mechanisms, but the collecting duct is unique in its mechanisms of iron capture focused on heme transport. Consequently, the nutritional requirement of the collecting duct IC matches an essential component of innate defense, namely heme sequestration.

Funding

  • NIDDK Support