Tongxinluo Inhibits Renal Fibrosis in Diabetic Nephropathy: Involvement of the Suppression of Intercellular Transfer of TGF-β1-Containing Exosomes from GECs to GMCs

Abstract

Glomerular mesangial cells (GMCs) activation is implicated in the pathogenesis of diabetic nephropathy (DN). Our previous study revealed that high glucose (HG)-treated glomerular endothelial cells (GECs) produce an increased number of TGF-[Formula: see text]1-containing exosomes to activate GMCs through the TGF-[Formula: see text]1/Smad3 signaling pathway. We also identified that Tongxinluo (TXL), a traditional Chinese medicine, has beneficial effects on the treatment of DN in DN patients and type 2 diabetic mice. However, it remained elusive whether TXL could ameliorate renal structure and function through suppression of intercellular transfer of TGF-[Formula: see text]1-containing exosomes from GECs to GMCs. In this study, we demonstrate that TXL can inhibit the secretion of TGF-[Formula: see text]1-containing exosomes from HG-treated GECs. Furthermore, exosomes produced by HG induced-GECs treated with TXL cannot trigger GMC activation, proliferation and extracellular matrix (ECM) overproduction both in vitro and in vivo. These results suggest that TXL can prevent the transfer of TGF-[Formula: see text]1 from GECs to GMCs via exosomes, which may be one of the mechanisms of TXL in the treatment of DN.

Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management

“…Renal fibrosis has been recognized as one of the most crucial processes for the development of DN from metabolism dysfunction, oxidative stress, inflammation, fibrosis, sclerosis, and ultimately ESRD. Accumulative studies revealed that renal fibrosis is highly correlated with enhanced synthesis, weakened degradation, and excessive deposition of the extracellular matrix, partially including collagen I/IV and fibronectin 93 , 96 , 150 . The TGF- β /small mothers against decapentaplegic (SMAD) and Janus kinase/signal transducers and activators of transcription/suppressor of cytokine signaling proteins (JAK/STAT/SOCS) signaling pathways, accompanied with angiotensin II, connective tissue growth factor (CTGF), matrix metallopeptidase 2 (MMP-2), bone morphogenetic protein-7 (BMP-7), and α smooth muscle actin ( α -SMA), are involved in regulative action of glomerular and tubulointerstitial fibrosis in DN 90 , 91 , 94 , 96 , 97 , 98 .…”

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…Podocytes were injured by EVs from glomerular endothelial cells (GEC) that had undergone endothelial-to-mesenchymal transition after exposure to high glucose as occurs in DN [ 118 ]. In vitro, EVs were produced at higher frequency by glucose-treated GEC and the EVs both promoted mesenchymal transition in podocytes by a process involving Wnt/β-catenin signaling [ 118 ] and stimulated activation of glomerular mesangial cells (GMC) by mechanisms that involve EV TGF-β levels [ 119 ] and EV delivery of PI3K/AKT- and MAPK-associated circular RNAs [ 120 ]. High glucose-treatment of GMC caused EVs to be produced at higher frequency and they caused injury in podocytes (increased apoptosis and TGF-β1/PI3-AKT signaling; reduced cell adhesion and expression of nephrin, podocin, and WT-1 [ 121 ] while stimulating fibrosis-related changes in control GMC (increased production of FN, angiotensin II (Ang II), renin, AT 1 /AT 2 ) [ 122 ].…”

Chinese Herbal Formulas and Renal Fibrosis: An Overview

“…Consistent results from numerous studies indicate that TGF-β1/Smads signal pathway can be inhibited by decreasing Smad2/3 and increasing Smad7 and these may have antifibrosis effects [64,65]. Above of all, targeting the TGF-β1downstream effectors or the signaling that mediates its fibrogenic action will become a new therapy in the treatment of renal fibrosis, and several Chinese herbal formulas are being developed for this purpose such as Shenqi Wan and Tongxin Luo [66,67].…”