PMID- 33245967 OWN - NLM STAT- MEDLINE DCOM- 20210402 LR - 20220421 IS - 1879-0631 (Electronic) IS - 0024-3205 (Linking) VI - 272 DP - 2021 May 1 TI - Loganin alleviates macrophage infiltration and activation by inhibiting the MCP-1/CCR2 axis in diabetic nephropathy. PG - 118808 LID - S0024-3205(20)31561-7 [pii] LID - 10.1016/j.lfs.2020.118808 [doi] AB - BACKGROUND/AIMS: The theory of inflammation is one of the important theories in the pathogenesis of diabetic nephropathy (DN). We herein aimed to explore whether loganin affected macrophage infiltration and activation upon diabetic nephropathy (DN) by a spontaneous DN mice and a co-culture system of glomerular mesangial cells (GMCs) and macrophage cells (RAW264.7) which was induced by advanced glycation end products (AGEs). METHODS AND KEY FINDINGS: Loganin showed remarkable capacity on protecting renal from damage by mitigating diabetic symptoms, improving the histomorphology of the kidney, decreasing the expression of extracellular matrix such as FN, COL-IV and TGF-beta, reversing the production of IL-12 and IL-10 and decreasing the number of infiltrating macrophages in the kidney. Moreover, loganin showed markedly effects by suppressing iNOS and CD16/32 expressions (M1 markers), increasing Arg-1 and CD206 expressions (M2 markers), which were the phenotypic transformation of macrophage. These effects may be attributed to the inhibition of the receptor for AGEs (RAGE) /monocyte chemotactic protein-1 (MCP-1)/CC chemokine receptor 2 (CCR2) signaling pathway, with significantly down-regulated expressions of RAGE, MCP-1 and CCR2 by loganin. Loganin further decreased MCP-1 secretion when RAGE was silenced, which means other target was involved in regulating the MCP-1 expression. While loganin combinated with the inhibitor of CCR2 exerted stronger anti-inhibition effects of iNOS expression, suggesting that CCR2 was the target of loganin in regulating the activation of macrophages. SIGNIFICANCE: Loganin could ameliorate DN kidney damage by inhibiting macrophage infiltration and activation via the MCP-1/CCR2 signaling pathway in DN. CI - Copyright (c) 2020. Published by Elsevier Inc. FAU - Du, Qiu AU - Du Q AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Pharmacy, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Fu, Ying-Xue AU - Fu YX AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Shu, An-Mei AU - Shu AM AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Lv, Xing AU - Lv X AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China; Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201210, China. FAU - Chen, Yu-Ping AU - Chen YP AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Gao, Yu-Yan AU - Gao YY AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Chen, Jing AU - Chen J AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Wang, Wei AU - Wang W AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Lv, Gao-Hong AU - Lv GH AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Lu, Jin-Fu AU - Lu JF AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. FAU - Xu, Hui-Qin AU - Xu HQ AD - School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory of Efficacy and Safety Evaluation of Traditional Chinese Medicine in Jiangsu Province, Nanjing 210023, China. Electronic address: hqxu309@sina.com. LA - eng PT - Journal Article DEP - 20201124 PL - Netherlands TA - Life Sci JT - Life sciences JID - 0375521 RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CCL8) RN - 0 (Fibronectins) RN - 0 (Glycation End Products, Advanced) RN - 0 (Iridoids) RN - 0 (Receptors, CCR1) RN - 0 (Receptors, CCR2) RN - 0 (Transforming Growth Factor beta1) RN - H7WJ16Q93C (loganin) SB - IM MH - Animals MH - Chemokine CCL2/metabolism/physiology MH - Chemokine CCL8/metabolism MH - Diabetes Mellitus, Experimental/metabolism MH - Diabetic Nephropathies/*drug therapy/metabolism MH - Fibronectins/metabolism MH - Glycation End Products, Advanced/metabolism MH - Iridoids/metabolism/*pharmacology MH - Kidney/metabolism MH - Macrophage Activation/drug effects MH - Macrophages/drug effects/*metabolism MH - Male MH - Mesangial Cells/metabolism MH - Mice MH - Mice, Inbred C57BL MH - RAW 264.7 Cells MH - Receptors, CCR1/metabolism MH - Receptors, CCR2/metabolism/physiology MH - Signal Transduction/drug effects MH - Transforming Growth Factor beta1/metabolism OTO - NOTNLM OT - CCR2 OT - Diabetic nephropathy OT - Glomerular mesangial cells OT - Loganin OT - MCP-1 OT - Macrophages OT - RAGE EDAT- 2020/11/28 06:00 MHDA- 2021/04/07 06:00 CRDT- 2020/11/27 20:08 PHST- 2020/06/07 00:00 [received] PHST- 2020/11/16 00:00 [revised] PHST- 2020/11/17 00:00 [accepted] PHST- 2020/11/28 06:00 [pubmed] PHST- 2021/04/07 06:00 [medline] PHST- 2020/11/27 20:08 [entrez] AID - S0024-3205(20)31561-7 [pii] AID - 10.1016/j.lfs.2020.118808 [doi] PST - ppublish SO - Life Sci. 2021 May 1;272:118808. doi: 10.1016/j.lfs.2020.118808. Epub 2020 Nov 24.