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        Simulating the physiological environment for kidney tubular crystallopathy in vitro utilizing uric acid.

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        Final Article, research project Chaja Klein.pdf (1.664Mb)
        Publication date
        2022
        Author
        Klein, Chaja
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        Summary
        Aberrant crystallization of uric acid (UA) in the kidney can cause an inflammatory re- sponse that is associated with the identification and progression of chronic kidney disease and end- stage renal failure. It had previously been reported that UA could trigger inflammatory responses by activating some transcription factors, such as Nuclear Factor-κB (NF-κB), and induce the expres- sion of proinflammatory cytokines of the interleukin-1 family, such as IL-1β and IL-18. Although the NLRP3-dependent inflammation by UA is studied in multiple cell types, simulation of the phys- iological environment for UA crystal formation in conditionally immortalized primary tubular epi- thelial cells (ciPTECs) and the down-stream inflammatory processes has not been well defined. Here, we evaluated the effect of UA on the activation of the NLRP3 inflammasome considering different pH levels and timepoints. Exposure of ciPTECS to UA in reduced pH levels resulted in more significant changes in cell viability across UA concentrations compared to physiological pH. Also, exposure to UA increased expression of IL-1β on protein level, particularly in lower pH levels. Furthermore, UA induced expression of Caspase-1, TNFα and ASC in a concentration-, and pH- dependent way. However, it was observed that expression of IL-1β and NLRP3 did not follow a concentration-dependent trend across some pH-levels. In this case, other mechanisms might be in- volved in UA induced IL-1β and NLRP3 mRNA expression. In conclusion, we showed that UA reduces viability in ciPTECs and inducing expression of inflammasome-mediated markers of caspase-1, ASC, TNFα on mRNA and IL-1β on protein level, particularly when UA concentrations were elevated and pH levels were lowered.
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        https://studenttheses.uu.nl/handle/20.500.12932/43085
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