DJC Suppresses Advanced Glycation End Products‐Induced JAK‐STAT Signaling and ROS in Mesangial Cells

Abstract

The antidiabetic properties and anti-inflammatory effects of Danzhi Jiangtang Capsules (DJC) have been demonstrated in clinical and laboratory experiments. In this study, we explored whether DJC can ameliorate advanced glycation end products- (AGEs-) mediated cell injury and the precise mechanisms of DJC in treating diabetic nephropathy (DN). Western blot analysis was employed to assess the expressions of iNOS, COX2, and SOCS and the phosphorylation of JAK2, STAT1, and STAT3 in glomerular mesangial cells (GMCs) after treatment with DJC. TNF-α, IL-6, and MCP-1 were determined using double-antibody sandwich ELISA. ROS and NADPH oxidase activity were measured by DCFH-DA assay and lucigenin-enhanced chemiluminescence, respectively. DJC significantly reversed the AGEs-induced expression of COX2 and iNOS. Moreover, DJC inhibited the AGEs-induced JAK2-STAT1/STAT3 activation, resulting in the inhibition of inflammatory cytokines such as IL-6, MCP-1, and TNF-α in a concentration-dependent manner. The ability of DJC to suppress STAT activation was also verified by the observation that DJC significantly increased the SOCS3 protein level. DJC reversed the AGEs-induced accumulation of ROS and NADPH oxidase activity, thus confirming that DJC possesses antioxidant activity. The results suggest that the anti-inflammatory effects of DJC in GMCs may be due to its ability to suppress the JAK2-STAT1/STAT3 cascades and reduce ROS production.

Danzhi Jiangtang Capsule ameliorates kidney injury <i>via </i>inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats

“…In our current study, the ability of DJC to inhibit JAK-STAT signaling was verified by the observation that it reversed the elevated protein expression level of SCOS-3 in renal tissues. We also reported a similar result in mesangial cells stimulated by AGEs (16). Our results indicate that the elevated SOCS proteins are involved in the activated JAK-STAT signaling in diabetic renal tissues.…”

“…DJC contains 6 medicinal components at a ratio of 6:5:4:4:3:3: Radix Pseudostellariae, Radix Rehmanniae, Cortex Moutan, Rhizoma Alismatis, Semen Cuscutae Chinensis, and Leech. As mentioned in the previous study (16), Cortex Moutan was extracted using ethanol and the extract was dried under vacuum. The gruffs of Cortex Moutan and the other 4 medicinal components except for Leech, were mixed and extracted with water.…”

The mechanism of mulberry leaves against renal tubular interstitial fibrosis through ERK1/2 signaling pathway was predicted by network pharmacology and validated in human tubular epithelial cells

“…Recent studies have painted an interesting picture on the emerging role of oxidative stress, whereby the excessive generation of ROS is associated with the structural and functional damage of various organs. Then, intracellular ROS generation has been reported to a potential mediator, which played an essential role in the induction of EMT and contributed to apoptosis in the progression of DN (Guo et al, ; Sun et al, ; Xu et al, ). Consistent with these studies, it has been confirmed in present study that high glucose conditions increased ROS generation.…”

The cardiovascular complications of diabetes: a striking link through protein glycation

“…Inflammatory factors enhance the development of extra AGEs through the AGE/RAGE axis leading to a vicious cycle of negative consequences on several issues such as tumor formation, amyloidosis, and neurodegeneration [20,27]. Another signaling cascade affected by AGE accumulation is the activation of the Janus kinase/ signal transducer and activator of transcription pathway (Jak/Stat) that is associated with inflammatory, cell apoptosis, and tumor formation [28,29]. Moreover, AGE/RAGE activation leads to a depletion in nitric oxide levels.…”

“…It has been reported that underexpression of AGE-R1 receptors is associated with diabetes mellitus complications and the induction of inflammation [24][25][26]. The sRAGE receptors include different subtypes: the endogenous secreted RAGE (esRAGE) and cleave type soluble RAGE (cRAGE) are the main ones [25][26][27][28]. Metalloproteinases can produce cRAGE from cleaving the RAGE receptor that is anchored in the cell membrane [31].…”