Esculin alleviates acute kidney injury and inflammation induced by LPS in mice and its possible mechanism

doi:10.5246/jcps.2020.05.030

Abstract

Abstract:

Acute kidney injury (AKI) is a common clinical serious illness. Esculin (ES) is a coumarin compound of traditional Chinese medicine Cortex Fraxini. Our previous study has found that ES protects against inflammation and renal damage in diabetic rats.In the present study, we aimed to investigate the effects and the possible mechanism of ES against lipopolysaccharides (LPS)-induced AKI in mice. Renal morphology was observed by H&E staining. Renal function was evaluated by blood urea nitrogen (BUN) level and creatinine content in serum. Inflammatory factor levels were measured by ELISA assay. The inflammatory proteins were analyzed by RT-PCR and Western blotting analysis. The results showed that ES alleviated LPS-induced pathological injury and renal dysfunction, and decreased BUN level and creatinine content in serum. In addition, ES significantly reduced the release of pro-inflammatory factors, including IL-1β, IL-6 and TNF-α, chemokine MCP-1 and cell adhesion molecule ICAM-1. Furthermore,the expressions of inflammatory pathway proteins P2X7, HMGB1, TLR4 and MyD88 both at the mRNA and protein levels were all down-regulated by ES in the kidney tissue of LPS-challenged mice. These results suggested ES protected against LPS-induced AKI through inhibiting P2X7 expression and HMGB1/TLR4 inflammatory pathway.

Key words: Acute kidney injury, Esculin, Lipopolysaccharide, Inflammation, Purinergic 2X7 receptor, High mobility group box 1

CLC Number:

R963

Supporting:

Xiao Cheng, Yinglin Yang, Weihan Li, Man Liu, Shanshan Zhang, Yuehua Wang, Guanhua Du. Esculin alleviates acute kidney injury and inflammation induced by LPS in mice and its possible mechanism[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(5): 322-332.

References

[1] Zager, R.A.; Johnson, A.C.; Lund, S.; Hanson, S. Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response. Am. J. Physiol. Renal Physiol. 2006, 291, F546-F556.

[2] Korkeila, M.; Ruokonen, E.; Takala, J. Costs of care, long-term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Intensive Care Med. 2000, 26, 1824-1831.

[3] Metnitz, P.G.; Krenn, C.G.; Steltzer, H.; Lang, T.; Ploder, J.; Lenz, K.; Le Gall, J.R.; Druml, W. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit. Care Med. 2002, 30, 2051-2058.

[4] Ricci, Z.; Polito, A.; Polito, A.; Ronco, C. The implications and management of septic acute kidney injury. Nat. Rev. Nephrol. 2011, 7, 218-225.

[5] Chowdhury, P.; Sacks, S.H.; Sheerin, N.S. Toll-like receptors TLR2 and TLR4 initiate the innate immune response of the renal tubular epithelium to bacterial products. Clin. Exp. Immunol. 2006, 145, 346-356.

[6] Yang, H.; Cheng, X.; Yang, Y.L.; Wang, Y.H.; Du, G.H. Ramulus Cinnamomi extract attenuates neuroinflammatory responses via downregulating TLR4/MyD88 signaling pathway in BV2 cells. Neural. Regen Res. 2017, 12, 1860-1864.

[7] Chuang, C.H.; Yang, C.K.; Wu, P.H.; Zhang, Y.; Yang, P.J. Acute renal injury induced by endotoxic shock in rats is alleviated via PI3K/Nrf2 pathway. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 5394-5401.

[8] Chen, Q.Y.; Wang, C.Q.; Yang, Z.W.; Tang, Q.; Tan, H.R.; Wang, X.; Cai, S.Q. Differences in anti-inflammatory effects between two specifications of Scutellariae Radix in LPS-induced macrophages in vitro. Chin. J. Nat. Med. 2017, 15, 515-524.

[9] Park, B.S.; Lee, J.O. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp. Mol. Med. 2013, 45, e66.

[10] Zhang, B.F.; Wang, P.F.; Cong, Y.X.; Lei, J.L.; Wang, H.; Huang, H.; Han, S.; Zhuang, Y. Anti-high mobility group box-1 (HMGB1) antibody attenuates kidney damage following experimental crush injury and the possible role of the tumor necrosis factor-α and c-Jun N-terminal kinase pathway. J. Orthop. Surg. Res. 2017, 12, 110.

[11] Deuchars, S.A.; Atkinson, L.; Brooke, R.E.; Musa, H.; Milligan, C.J.; Batten, T.F.; Buckley, N.J.; Parson, S.H.; Deuchars, J. Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J. Neurosci. 2001, 21, 7143-7152.

[12] Turner, C.M.; Tam, F.W.; Lai, P.C.; Tarzi, R.M.; Burnstock, G.; Pusey, C.D.; Cook, H.T.; Unwin, R.J. Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis. Nephrol. Dial. Transplant. 2007, 22, 386-395.

[13] Wang, Y.H.; Liu, Y.H.; He, G.R.; Lv, Y.; Du, G.H. Esculin improves dyslipidemia, inflammation and renal damage in streptozotocin-induced diabetic rats. BMC Complement Altern. Med. 2015, 15, 402.

[14] Niu, X.F.; Wang, Y.; Li, W.F.; Zhang, H.L.; Wang, X.M.; Mu, Q.L.; He, Z.H.; Yao, H. Esculin exhibited anti-inflammatory activities in vivo and regulated TNF-α and IL-6 production in LPS-stimulated mouse peritoneal macrophages in vitro through MAPK pathway. Int. Immunopharmacol. 2015, 29, 779-786.

[15] Zhang, L.; Sun, D.D.; Bao, Y.; Shi, Y.; Cui, Y.; Guo, M.H. Nerolidol protects against LPS-induced acute kidney injury via inhibiting TLR4/NF-κB signaling. Phytother. Res. 2017, 31, 459-465.

[16] Mei, S.Q.; Livingston, M.; Hao, J.L.; Li, L.; Mei, C.L.; Dong, Z. Autophagy is activated to protect against endotoxic acute kidney injury. Sci. Rep. 2016, 6, 22171.

[17] Xiao, C. Xiao-Xu-Ming decoction extract alleviates LPS-induced neuroinflammation associated with down-regulating TLR4/MyD88 signaling pathway in vitro and in vivo. J. Chin. Pharm. Sci. 2019, 28, 88-99.

[18] Cheng, X.; Yang, Y.L.; Yang, H.; Wang, Y.H.; Du, G.H. Kaempferol alleviates LPS-induced neuroinflammation and BBB dysfunction in mice via inhibiting HMGB1 release and down-regulating TLR4/MyD88 pathway. Int. Immunopharmacol. 2018, 56, 29-35.

[19] Ostermann, M.; Chang, R.W.S. Acute kidney injury in the intensive care unit according to RIFLE. Crit. Care. Med. 2007, 35, 1837-1843.

[20] Wan, L.; Bagshaw, S.M.; Langenberg, C.; Saotome, T.; May, C.; Bellomo, R. Pathophysiology of septic acute kidney injury: what do we really know? Crit. Care. Med. 2008, 36, S198-S203.

[21] Doi, K.; Leelahavanichkul, A.; Yuen, P.S.; Star, R.A. Animal models of Sepsis and Sepsis-induced kidney injury. J. Clin. Invest. 2009, 119, 2868-2878.

[22] Chvojka, J.; Sýkora, R.; Karvunidis, T.; Raděj, J.; Kroužecký, A.; Novák, I.; Matějovič, M. New developments in septic acute kidney injury. Physiol. Res. 2010, 59, 859-869.

[23] Chertow, G.M.; Burdick, E.; Honour, M.; Bonventre, J.V.; Bates, D.W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol. 2005, 16, 3365-3370.

[24] Cruz, D.N.; Bellomo, R.; Ronco, C. Clinical effects of polymyxin B-immobilized fiber column in septic patients. Contrib. Nephrol. 2007, 156, 444-451.

[25] Prowle, J.R.; Kolic, I.; Purdell-Lewis, J.; Taylor, R.; Pearse, R.M.; Kirwan, C.J. Serum creatinine changes associated with critical illness and detection of persistent renal dysfunction after AKI. Clin. J. Am. Soc. Nephrol. 2014, 9, 1015-1023.

[26] Fu, H.Y.; Hu, Z.S.; Di, X.W.; Zhang, Q.H.; Zhou, R.B.; Du, H.Y. Tenuigenin exhibits protective effects against LPS-induced acute kidney injury via inhibiting TLR4/NF-κB signaling pathway. Eur. J. Pharmacol. 2016, 791, 229-234.

[27] Kang, K.P.; Kim, D.H.; Jung, Y.J.; Lee, A.S.; Lee, S.; Lee, S.Y.; Jang, K.Y.; Sung, M.J.; Park, S.K.; Kim, W. Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol. Dial. Transplant. 2009, 24, 3012-3020.

[28] Tan, S.F.; Wang, G.F.; Guo, Y.P.; Gui, D.K.; Wang, N.S. Preventive effects of a natural anti-inflammatory agent, astragaloside IV, on ischemic acute kidney injury in rats. Evid. Based Complement. Alternat. Med. 2013, 2013, 284025.

[29] Kashiwada, M.; Shirakata, Y.; Inoue, J.I.; Nakano, H.; Okazaki, K.; Okumura, K.; Yamamoto, T.; Nagaoka, H.; Takemori, T. Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway. J. Exp. Med. 1998, 187, 237-244.

[30] Hämäläinen, M.; Nieminen, R.; Vuorela, P.; Heinonen, M.; Moilanen, E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators. Inflamm. 2007, 2007, 45673.

[31] Vonend, O.; Turner, C.M.; Chan, C.M.; Loesch, A.; Carmen Dell’Anna, G.; Srai, K.S.; Burnstock, G.; Unwin, R.J. Glomerular expression of the ATP-sensitive P2X7 receptor in diabetic and hypertensive rat models. Kidney Int. 2004, 66, 157-166.

[32] Zhao, J.J.; Wang, H.Y.; Dai, C.; Wang, H.Y.; Zhang, H.; Huang, Y.F.; Wang, S.; Gaskin, F.; Yang, N.S.; Fu, S.M. P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis. Rheum. 2013, 65, 3176-3185.

[33] Thakur, V.; Nargis, S.; Gonzalez, M.; Pradhan, S.; Terreros, D.; Chattopadhyay, M. Role of glycyrrhizin in the reduction of inflammation in diabetic kidney disease. Nephron. 2017, 137, 137-147.

[34] Zhang, H.; Zhang, R.; Chen, J.; Shi, M.; Li, W.; Zhang, X.C. High mobility group Box1 inhibitor glycyrrhizic acid attenuates kidney injury in streptozotocin-induced diabetic rats. Kidney Blood Press. Res. 2017, 42, 894-904.

[35] Akira, S.; Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 2004, 4, 499-511.

[36] Brown, J.; Wang, H.; Martin, M.; Martin, M. TLR-signaling networks an integration of adaptor molecules, kinases, and cross-talk. J. Dental. Res. 2011, 90, 417-427.

[37] O’Neill, L.A. The role of MyD88-like adapters in Toll-like receptor signal transduction. Biochem. Soc. Trans. 2003, 31, 643-647.

[38] Kurashima, Y.; Kiyono, H. New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development. Exp. Mol. Med. 2014, 46, e83.

[39] Taylor, S.R.; Turner, C.M.; Elliott, J.I.; McDaid, J.; Hewitt, R.; Smith, J.; Pickering, M.C.; Whitehouse, D.L.; Cook, H.T.; Burnstock, G.; Pusey, C.D.; Unwin, R.J.; Tam, F.W. P2X7 deficiency attenuates renal injury in experimental glomerulonephritis. J. Am. Soc. Nephrol. 2009, 20, 1275-1281.