Abstract
Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1β (5 ng/mL) and high glucose (30 mmol/L). IL-1β treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1β-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81470957), the Natural Science Foundation of Jiangsu Province (No BK20141343), the Jiangsu Province Six Talent Peaks Project (No 2015-WSN-002), the project for Jiangsu Provincial Medical Talent (No ZDRCA2016077), the Fundamental Research Funds for the Central Universities (No KYZZ15-0061), the Jiangsu Province Ordinary University Graduate Research Innovation Project (No SJZZ16-004), and the Clinical Medical Science Technology Special Project of Jiangsu Province (No BL2014080).
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Hu, Zb., Ma, Kl., Zhang, Y. et al. Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy. Acta Pharmacol Sin 39, 1022–1033 (2018). https://doi.org/10.1038/aps.2017.177
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DOI: https://doi.org/10.1038/aps.2017.177
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