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Calcium Pyrophosphate And Monosodium Urate Activate The NLRP3 Inflammasome Within Bladder Urothelium Via Reactive Oxygen Species And TXNIP.

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Date
2019-01
Authors
Harper, Shelby N
Leidig, Patrick D
Hughes, Francis M
Jin, Huixia
Purves, J Todd
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Abstract
Objective:To investigate the in vitro activation of the NLRP3 inflammasome within bladder urothelium by stone-forming components. Further, to describe the contributions of reactive oxygen species (ROS) and thioredoxin-interacting protein (TXNIP), an important structural component of the inflammasome, to this activation. Methods:Urothelial cells were harvested and incubated overnight. For agonist studies, cells were treated with varying concentrations of calcium pyrophosphate (CPPD) and monosodium urate (MSU). For inhibitor studies, cells were treated with either N-acetylcysteine (NAC) (1 hr) or Verapamil (4 hrs) prior to incubation with either CPPD (62.5 ug/mL) or MSU (1.25 ug/mL) for 24 hrs. Untreated controls were incubated with ATP (1.25 mM) for 1 hr to maximally stimulate NLRP3 inflammasome activity (measured as caspase-1 cleavage of the fluorogenic substrate Ac-YVAD-AFC). Results are reported as a percentage of maximum ATP response. Results:CPPD and MSU activate caspase-1 in urothelial cells in a dose-dependent manner, reaching ~50% and ~25% of the ATP response, respectively. Pre-treatment with the general ROS scavenger NAC reduces this activation in a dose-dependent manner. Additionally, activation was suppressed through treatment with Verapamil, a known downregulator of TXNIP expression. Conclusion:The stone components CPPD and MSU activate NLRP3 in an ROS and TXNIP-dependent manner in bladder urothelium. These findings demonstrate the importance of ROS and TXNIP, and suggest that targeting either may be a way to decrease stone-dependent NLRP3 inflammation within the bladder.
Type
Journal article
Subject
NLRP3 inflammasome
ROS
TXNIP
inflammation
stones
urothelium
Permalink
https://hdl.handle.net/10161/21292
Published Version (Please cite this version)
10.2147/RRU.S225767
Publication Info
Harper, Shelby N; Leidig, Patrick D; Hughes, Francis M; Jin, Huixia; & Purves, J Todd (2019). Calcium Pyrophosphate And Monosodium Urate Activate The NLRP3 Inflammasome Within Bladder Urothelium Via Reactive Oxygen Species And TXNIP. Research and reports in urology, 11. pp. 319-325. 10.2147/RRU.S225767. Retrieved from https://hdl.handle.net/10161/21292.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Hughes

Monty Hughes Jr.

Assistant Professor in Surgery
 Dr. Hughes received his Ph.D. from the Medical University of South Carolina and was a post doc at both the University of North Carolina at Chapel Hill and NIH. He then joined the faculty of the University of North Carolina at Charlotte where he rose to the rank of Associate Professor (with tenure). Following a brief stint as the director of the biology division of a start-up pharmaceutical company, he joined forces with Dr. Purves at the Medical University of South Carolina to begin this l
Leidig

Patrick Leidig

House Staff
Purves

J Todd Purves

Associate Professor of Surgery
Alphabetical list of authors with Scholars@Duke profiles.
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