Role of Hypoxia Inducible Factor-1? (HIF-1?) in Innate Defense against Uropathogenic Escherichia coli Infection.

ABSTRACT: Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTI) affecting approximately 150 million people worldwide. Here, we revealed the importance of transcriptional regulator hypoxia-inducible factor-1 ? subunit (HIF-1?) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1? stabilizing agent, were studied using human uroepithelial cells (5637) and a murine UTI model. UPEC adherence and invasion were significantly reduced in 5637 cells when HIF-1? protein was allowed to accumulate. Uroepithelial cells treated with AKB-4924 also experienced reduced cell death and exfoliation upon UPEC challenge. In vivo, fewer UPEC were recovered from the urine, bladders and kidneys of mice treated transurethrally with AKB-4924, whereas increased bacteria were recovered from bladders of mice with a HIF-1? deletion. Bladders and kidneys of AKB-4924 treated mice developed less inflammation as evidenced by decreased pro-inflammatory cytokine release and neutrophil activity. AKB-4924 impairs infection in uroepithelial cells and bladders, and could be correlated with enhanced production of nitric oxide and antimicrobial peptides cathelicidin and ?-defensin-2. We conclude that HIF-1? transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1? boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI.

SUBMITTER: Lin AE 

PROVIDER: S-EPMC4415805 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature