2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from the root of Averrhoa carambola L., protects against diabetic kidney disease by inhibiting TLR4/TGFŒ≤ signaling pathway
Authors: Luhui Jiang
Yuchun Li
Xin Zhou
Luhui Qin
Xiang Huang
Renbin Huang
Shunyu Lu
Hongliang Zhang
Jinbin Wei
Lixiu Chen
Xingchun Wu
Peiyu Liao
Journal: International Immunopharmacology (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: DMDD; Diabetic kidney disease; Smad2/3; TGFŒ≤; TLR4.
Affiliations: Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China; Pharmaceutical College, Guangxi Medical University, Nanning 530021, Guangxi, China., Pharmaceutical College, Guangxi Medical University, Nanning 530021, Guangxi, China., Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China., Shenzhen High School of Science (Sendelta International Academy), Shenzhen, China., Pharmaceutical College, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address: .

Abstract:  Objective: Diabetic kidney disease (DKD) is the leading cause of death and disability of diabetes mellitus. However, there is still a lack of specific drugs for the treatment of DKD. The chief aim of this research is to investigate the role and mechanism of 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) for DKD. Methods: Wild type and TLR4 knockout mice were induced to diabetes. After 4-week treatment with DMDD, blood sugar, renal function, blood lipid and pathological changes were assessed. Real-time PCR, western blotting, and immunohistochemistry were employed to detect the expressions of TLR4, TGFŒ≤1 and Smad2/3 in the renal tissue. Results: DMDD improved the serum lipid and decreased fasting blood glucose levels in diabetic mice. CysC and urinary albumin levels increased markedly in the diabetic group, and they were obviously decreased after 4 weeks of DMDD treatment. Compared with the WT diabetic mice, the urinary albumin and CysC in the TLR4-/- mice were expressed at lower levels. HE and Masson's staining revealed that DMDD clearly ameliorated pathological changes and renal fibrosis. When TLR4 gene was knock out, the pathological was improved. Mechanistically, TLR4, TGF-Œ≤1 and Smad2/3 were obvious up-regulation in the renal tissues of diabetic mice. The expressions of these proteins were significantly down-regulated after DMDD treatment (p &lt; 0.05). In the TLR4-/- mice, mRNA and protein levels of TGF-Œ≤1 and Smad2/3 were obviously lower than those in the WT mice. In addition, IHC revealed that a strong in situ expressions of TLR4, TGF-Œ≤1 and Smad2/3 were seen in the kidney tissues of diabetic mice, which were distinctly weakened in the DMDD-treated mice. In the TLR4-/- mice, however, expressions of TGF-Œ≤1 and Smad2/3 were not remarkable increase in the diabetic mice compared with normal mice. Conclusions: These results strongly indicate that TLR4 is essential for DMDD protection against renal dysfunction in diabetic mice. Its hypoglycemic and anti-fibrosis effects were likely mediated by the TLR4/TGFŒ≤ signaling pathway. 

Retracted: No

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