An Indole-2-Carboxamide Derivative, LG4, Alleviates Diabetic Kidney Disease Through Inhibiting MAPK-Mediated Inflammatory Responses

Aim: Elevated infammatory signaling has been shown to play an important role in diabetic kidney disease (DKD). We previously developed a new anti-infammatory compound LG4. In the present study, we have tested the hypothesis that LG4 could prevent DKD by suppressing inflammation and identifed the und...

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Bibliographic Details
Published inJournal of inflammation research Vol. 14; p. 1613
Main Authors Qian, Jianchang, Yin, Sihui, Ye, Lin, Wang, Zhe, Shu, Sheng, Mou, Zhenxin, Xu, Mingjiang, Chattipakorn, Nipon, Liu, Zhiguo, Liang, Guang
Format Journal Article
LanguageEnglish
Published Dove Medical Press Limited 30.04.2021
Subjects
Binding proteins
Blood sugar
Hyperglycemia
Inflammation
Kidney diseases
Protein binding
Type 1 diabetes
Canada
China
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Summary:Aim: Elevated infammatory signaling has been shown to play an important role in diabetic kidney disease (DKD). We previously developed a new anti-infammatory compound LG4. In the present study, we have tested the hypothesis that LG4 could prevent DKD by suppressing inflammation and identifed the underlying mechanism. Methods: Streptozotocin-induced type 1 diabetic mice were used to develop DKD and evaluate the effects of LG4 against DKD. To identify the potential targets of LG4, biotinlinked LG4 was synthesized and subjected to proteome microarray screening. The cellular mechanism of LG4 was investigated in HG-challenged SV40MES13 cells. Results: Although LG4 treatment had no effect on the body weight and blood glucose levels, it remarkably reversed the hyperglycemia-induced pathological changes and fibrosis in the kidneys of T1DM mice. Importantly, hyperglycemia-induced renal inflammation evidenced by NF-[kappa]B activation and TNF[alpha] and IL-6 overexpression was greatly ameliorated with LG4 treatment. Proteosome microarray screening revealed that JNK and ERK were the direct binding proteins of LG4. LG4 significantly reduced HG-induced JNK and ERK phosphorylation and subsequent NF-[kappa]B activation in vivo and in vitro. In addition, LG4 did not show further anti-infammatory effect in HG-challenged mesangial cells with the presence of JNK or ERK inhibitor. Conclusion: LG4 showed renoprotective activity through inhibiting ERK/JNK-mediated inflammation in diabetic mice, indicating that LG4 may be a therapeutic agent for DKD. Keywords: indole-2-carboxamide derivative, diabetic kidney disease, inflammation, MAPK, NF-[kappa]B
ISSN:1178-7031
1178-7031