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bioRxiv · 10.1101/2022.03.12.484115

Hyperuricemia triggers Renal Tubular Epithelial Pyroptosis by using ROS to activate the NLRP3 inflammasome

Wu, Y.·Li, R.·Li, D.·Ou, J.·Zhou, J.·Wang, C.·Gao, J.
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Abstract

Renal injury resulting from hyperuricemia has gained a lot of interest. Pyroptosis refers to inflammatory cell death. The activated caspase-1 cleavage, and the pivotal protein - GSDMD could have an association with the hyperuricemic kidney lesion pathogenesis. ROS is a vital NLRP3 inflammasome antagonist in various cells. We investigated the mechanism through which ROS stimulates NLRP3 to modulate pyroptosis in renal tubular epithelial cells as well as hyperuricemic rat kidneys. MethodsIn vitro cultured renal tubular epithelial cells (NRK-52E cells) were incubated with a gradient concentration of uric acid for 24 hr to investigate the pyroptosis through flow cytometry. Next, we used the inhibitors of ROS, mitochondrial ROS, NLRP3 and Caspase-1 respectively to intervene in uric acid treated cells to analyse pyproptosis and activation of ROS- NLRP3 inflammasome signal pathway. Finally, we evaluated the mechanism of hyperuricemia triggering renal tubular epithelial pyroptosis in rat kidney tissues. ResultsThe levels of ROS and mitochondrial ROS, the mRNA and protein expression of pyroptosis-associated factors Caspase-1 (p45, p20/10), NLRP3, and GSDMD were upregulated in uric acid, the induced NRK-52E cells as well as hyperuricemic model kidneys. The inhibition of ROS, mitochondrial ROS, NLRP3, or caspase-1 in the uric acid-induced NRK-52E cells may help in controlling pyroptosis. The expression of mRNA and protein by the cytokines IL-18 and IL-1{beta} also increased. ConclusionsGenerally, hyperuricemia triggered renal tubular epithelial pyroptosis via excessive ROS to modulate NLRP3 inflammasome activation in uric acid stimulated renal tubular epithelial cells as well as the oxonic acid potassium induced hyperuricemia.

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Wu, Y., Li, R., Li, D., Ou, J., Zhou, J., Wang, C., Gao, J.. 2022-03-13. Hyperuricemia triggers Renal Tubular Epithelial Pyroptosis by using ROS to activate the NLRP3 inflammasome. https://doi.org/10.1101/2022.03.12.484115

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