Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation

Abstract

Prostasin is a glycosylphosphatidylinositol-anchored serine protease, with epithelial sodium channel activation and tumor invasion suppression activities. We identified the bladder as an expression site of prostasin. In the mouse, prostasin mRNA expression was detected by reverse transcription and real-time polymerase chain reaction in the bladder, and the prostasin protein was localized by immunohistochemistry in the urothelial cells. In mice injected intraperitoneally with bacterial lipopolysaccharide (LPS), bladder prostasin mRNA expression was downregulated, whereas the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interferon-gamma (IFN-gamma), TNF-alpha, IL-1beta, and IL-6 was upregulated. Viral promoter-driven expression of the human prostasin homolog in the bladder of transgenic mice attenuated the LPS induction of iNOS but did not abolish the induction. LPS induction of COX-2, TNF-alpha, IL-1beta, and IL-6 expression, however, was not reduced by prostasin transgene expression. Liposome-mediated delivery of prostasin-expressing plasmid into mouse bladder produced similar attenuation effects on LPS-induced iNOS expression, while not affecting COX-2 or cytokine induction. Mice receiving plasmid expressing a catalytic mutant prostasin did not manifest the iNOS induction attenuation phenotype. We propose a proteolytic mechanism for prostasin to intercept cytokine signaling during LPS-induced bladder inflammation.

Uropathogenic Escherichia coli -Induced Inflammation Alters Mouse Urinary Bladder Contraction via an Interleukin-6-Activated Inducible Nitric Oxide Synthase-Related Pathway

“…The experimental urinary bladder infection models including intraperitoneal injection and intravesical instillation with E. coli or endotoxin were used in the present study as described previously (9,23,39,40). Adult female mice (ICR strain, 25 to 30 g) were used for all experiments.…”

“…Infection of the urinary tract results in an inflammatory response characterized by increased levels of urinary cytokines and neutrophil influx (2, 6). In rodent or mouse urinary tract infection models, which involved treatment with E. coli lipopolysaccharide (LPS) by intravesical instillation or intraperitoneal injection, induced interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expressions occurred within 4 to 24 h (9,23,29). It has been found that intravesical NO donors were capable suppressing bladder hyperactivity induced by cyclophosphamide-induced cystitis (25).…”

Urinary prostasin in humans: relationships among prostasin, aldosterone and epithelial sodium channel activity

“…13 This protein is abundantly present in the seminal fluid, urine and prostate gland, and it is also present at moderate levels in the kidney, bladder, lung, colon, pancreas, salivary gland, bronchi, liver and endometrium. 10,11,[14][15][16] Prostasin has been identified as a potential regulator of amiloride-sensitive ENaC function in the kidney, lung and airways. [17][18][19][20][21][22][23] However, the physiological role of this protein remains largely undetermined, although dysregulation of prostasin expression has been found in high-grade human prostate and breast cancers.…”

Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge

“…TNF-␣ is an important mediator of LPSinduced ARF and is also implicated in induction of hypothermia, a hallmark of the rodent response to endotoxemia and a reliable parameter for evaluating the acute effects of LPS (10,19,20,34,37). The injurious effects of LPS are also readily apparent on transurethral administration of LPS, which produces a localized inflammatory response that resembles urinary tract infection (UTI) and consists of extensive leukocyte infiltration, edema, and urothelial disruption in the bladder tissue (17,43).…”