title: Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway.
abstract: Urate crystals activate innate immunity through Toll like receptor 4 (TLR4) activation, leading to the formation of the NACHT, LRR and PYD domains-containing protein 3 [NALP3; also known as NOD-like receptor family, pyrin domain containing 3 (NALP3) and cryopyrin] inflammasome, caspase-1 activation and interleukin (IL)-1β expression in gout. However, whether elevated serum uric acid (UA) levels are associated with the development and progression of renal diseases without renal urate crystal deposition remains unknown. In the present study, human primary renal proximal tubule epithelial cells were incubated with soluble UA (100 µg/ml) with or without the TLR4 inhibitor, TAK242 (1 µM). The gene expression and protein synthesis of TLR4, NALP3, caspase-1, IL-1β and intercellular adhesion molecule-1 (ICAM-1) were detected by real-time PCR, ELISA, western blot analysis and fluorescence-activated cell sorting (FACS), respectively. Soluble UA significantly enhanced TLR4, NALP3, caspase-1, IL-1β and ICAM-1 expression in the human primary renal proximal tubule epithelial cells. The TLR4 inhibitor, TAK242 effectively blocked the soluble UA-induced upregulation of TLR4, NALP3, caspase-1, IL-1β and ICAM-1 expression in the human primary renal proximal tubule epithelial cells. Our findings indicate that soluble UA enhances NALP3 expression, caspase-1 activation, IL-1β and ICAM-1 production in renal proximal tubule epithelial cells in a TLR4-dependent manner, suggesting the activation of innate immunity in human primary renal proximal tubule epithelial cells by soluble UA.
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Jing
authors: J
authors: Xiao
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Xiao-Li
authors: XL
authors: Zhang
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Chensheng
authors: C
authors: Fu
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Rui
authors: R
authors: Han
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Weijun
authors: W
authors: Chen
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Yijun
authors: Y
authors: Lu
authors: Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China.
authors: Zhibin
authors: Z
authors: Ye
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid