Qiu Du1, Ying-Xue Fu2, An-Mei Shu2, Xing Lv3, Yu-Ping Chen2, Yu-Yan Gao2, Jing Chen2, Wei Wang2, Gao-Hong Lv2, Jin-Fu Lu2, Hui-Qin Xu4. 1. 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. 2. 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. 3. 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. 4. 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.
Abstract
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-β, 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.
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-β, 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.
Authors: Chelsy L Cliff; Bethany M Williams; Christos E Chadjichristos; Ulrik Mouritzen; Paul E Squires; Claire E Hills Journal: Int J Mol Sci Date: 2022-01-06 Impact factor: 5.923