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 α subunit (HIF-1α) in innate defense against UPEC-mediated UTI. The effects of AKB-4924, a HIF-1α 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-1α 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-1α 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 β-defensin-2. We conclude that HIF-1α transcriptional regulation plays a key role in defense of the urinary tract against UPEC infection, and that pharmacological HIF-1α boosting could be explored further as an adjunctive therapy strategy for serious or recurrent UTI.
Highlights
Urinary tract infection (UTI) is a very common and frequently recurrent bacterial disease accounting for approximately 8 million doctor visits per year, with an estimated total cost of $450 million annually in the United States [1,2]
uropathogenic E. coli (UPEC) colonization and invasion triggers an acute inflammatory response in the bladder epithelium leading to release of multiple pro-inflammatory cytokines including interleukin 6 (IL-6) and IL-1β, and chemokines such as IL-8 [6,7,8,9,10], and recruitment of neutrophils, which appear in the urine [11,12]
We found that treatment with 20 μM AKB-4924 for 2 h significantly increased Hypoxia Inducible Factor-1α (HIF-1α) protein abundance in healthy human uroepithelial cell line 5637 (ATCC HTB-9), comparable to the effect of the hallmark HIF-1α agonist desferrioxamine mesylate (DFO) (Fig 1A)
Summary
Urinary tract infection (UTI) is a very common and frequently recurrent bacterial disease accounting for approximately 8 million doctor visits per year, with an estimated total cost of $450 million annually in the United States [1,2]. The invasive pathogen uropathogenic E. coli (UPEC) is a primary etiologic agent of UTI, causing severe bladder infection (cystitis) and acute kidney infections (pyelonephritis) [4,5]. The inflammatory consequences of this early innate immune response can promote structural damage and cell death, including rapid shedding of the superficial uroepithelial cell layer lining the surface of the bladder lumen, which is a hallmark of UPEC infection [13,14]. Pro-inflammatory activation is an important first line of defense against pathogens, an excessive response can promote chronic cystitis and acute or chronic pyelonephritis [15,16,17,18]
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