Abstract
Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently. AB38b is a newly synthesized biphenyl diester derivative with a Nrf2 activation property. This research aims to evaluate the renal protective effects of AB-38b and to elucidate the anti-inflammation mechanisms involved. Type 2 diabetic mice induced by high fat diet with streptozocin (STZ) and high glucose-cultured mouse glomerular mesangial cells (GMCs) were used in current study. Results showed that administration of AB-38b improved the kidney function while attenuated renal fibrosis progression in diabetic mice together with reducing the extracellular matrix (ECM) accumulation of GMCs cultured in high glucose. Mechanistically, treatment with AB-38b significantly decreased the high level of NLRP3 inflammasome in diabetic condition by inhibiting the ROS/TXNIP/NLRP3 signaling pathway. And meanwhile, AB-38b treatment effectively improved Nrf2 signaling during diabetic condition. Furthermore, knocking down the gene expression of Nrf2 by siRNA in GMCs abolished the inhibition effect of AB-38b on NLRP3 inflammasome activation and ECM accumulation. Taken together, our data suggest that AB-38b was able to improve the renal function of diabetic mice, and the NLRP3 inflammasome inhibition effect of AB-38b was responsible for the renal protective effect. Further exploration indicate that Nrf2 plays pivotal role in AB-38b’s attenuation of DN progression through inhibiting NLRP3 inflammasome activation.
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22 January 2020
A Correction to this paper has been published: https://doi.org/10.1007/s10565-020-09512-w
16 February 2022
A Correction to this paper has been published: https://doi.org/10.1007/s10565-022-09696-3
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Funding
The work was financially supported by the National Natural Science Foundation of China (No. 81473257), the Qing Lan project, the Natural Science Foundation of Jiangsu Province (No. BK20151155), the “333” Foundation of Jiangsu Province (No. BRA2015329), the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China (No. 15KJA310005), and The Science and Technology project of Xuzhou (No. KC18202).
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Du, L., Wang, J., Chen, Y. et al. Novel biphenyl diester derivative AB-38b inhibits NLRP3 inflammasome through Nrf2 activation in diabetic nephropathy. Cell Biol Toxicol 36, 243–260 (2020). https://doi.org/10.1007/s10565-019-09501-8
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DOI: https://doi.org/10.1007/s10565-019-09501-8