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. 2019 Aug 7:12:1355-1363.
doi: 10.2147/DMSO.S209436. eCollection 2019.

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione isolated from Averrhoa carambola L. root ameliorates diabetic nephropathy by inhibiting the TLR4/MyD88/NF-κB pathway

Shunyu Lu #  1 , Hongliang Zhang #  1 , Xiaojie Wei  1 , Xiang Huang  1 , Lixiu Chen  1 , Luhui Jiang  1 , Xingchun Wu  1 , Xing Zhou  1 , Luhui Qin  1 , Yuchun Li  1 , Xing Lin  1 , Renbin Huang  1
Affiliations

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione isolated from Averrhoa carambola L. root ameliorates diabetic nephropathy by inhibiting the TLR4/MyD88/NF-κB pathway

Shunyu Lu et al. Diabetes Metab Syndr Obes. .

Erratum in

Abstract

Background: Averrhoa carambola L. is a traditional medicinal herb that has long been used to treat diabetes. Our previous studies found that 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from A. carambola L. roots could ameliorate diabetic nephropathy (DN), but its exact mechanism remains unclear.

Methods: A DN model was established by streptozotocin (STZ, 100 mg/kg body weight) in TLR4 knockout (TLR4-/-, KO) mice and wild-type (WT) mice. Body weight and blood glucose were evaluated after oral administration of DMDD (12.5, 25, 50 mg/kg body weight/d) in diabetic mice. The levels of serum lipids, including TC, TG, HDL, and LDL and kidney function indexes Scr and BUN, were detected by biochemical equipment. The levels of inflammatory cytokines including IL-6 and TNF-α, were determined by ELISA kits. Furthermore, changes in renal ultrastructure were observed by electron microscopy. Western blot analysis and RT-PCR were used to assess the protein expression and mRNA levels of TLR4, MyD88 and NF-κB.

Results: DMDD treatment attenuated diabetic nephropathy, as a result of a decline in blood glucose, serum creatinine, and blood urine nitrogen levels and an increase in the quantity and density of podocytes, combined with improved dyslipidaemia. DMDD treatment inhibited the inflammatory response and downregulated the expression of the TLR4/MyD88/NF-κB pathway in diabetic mice, and these changes were significantly different in TLR4-/- mice.

Conclusion: DMDD alleviates diabetic nephropathy by mitigating kidney damage and inflammation via the inhibition of the TLR4/MyD88/NF-κB signalling pathway.

Keywords: 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; TLR4/MyD88/NF-κB signalling pathway; diabetic nephropathy.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Effect of DMDD on the body weight of the WT and KO groups (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). The data are presented as the mean ± SEM. A, B, D, and E: compared with those of the same period of the normal control group (P<0.05); a, b, d, and e: compared with those of the same period of the diabetic nephropathy group (P<0.05). Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; WT, wild type; KO, knockout.
Figure 2
Figure 2
Effect of DMDD on the blood glucose level of the WT and KO groups (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). The data are presented as the mean ± SEM. A, B, D, E, and F: compared with those of the same period of the normal control group (P<0.05). d, e, and f: compared with those of the same period of the diabetic nephropathy group (P<0.05). Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; WT, wild type; KO, knockout.
Figure 3
Figure 3
Effect of DMDD on IPGTT and ITT (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). *P<0.05: compared with the normal control groups. #P<0.05: compared with the diabetic nephropathythy groups. Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; IPGTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test.
Figure 4
Figure 4
Effect of DMDD on the renal function of diabetic mice (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). A and B compared with the normal control groups (P<0.05); a, b: compared with the diabetic nephropathy groups (P<0.05). Abbreviation: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 5
Figure 5
Effect of DMDD on the levels of TC, TG, HDL, and LDL in the serum (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). A and B: compared with the normal control groups (P<0.05); a, b: compared with the diabetic nephropathy groups (P<0.05). Abbreviation: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 6
Figure 6
Effect of DMDD on the levels of IL-6 and TNF-α in kidney tissue (n=6). NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). A and B: compared with the normal control groups (P<0.05); a and b :compared with the diabetic nephropathy groups (P<0.05). #: compared with WT mice( P<0.05). Abbreviation: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 7
Figure 7
Effect of DMDD on the ultrastructural changes in the renal tissue of WT and KO mice. NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; WT, wild type; KO, knockout.
Figure 8
Figure 8
Effect of DMDD on the mRNA levels of TLR4, MyD88, and NF-κB. NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). A and B: compared with the WT and KO normal controls (P<0.05); a and b: compared with the WT and KO diabetic nephropathy groups (P<0.05); and #: compared with WT mice (P<0.05). Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; WT, wild type; KO, knockout.
Figure 9
Figure 9
Effect of DMDD on the expression of proteins in the TLR4/MyD88/NF-κB pathway. NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). Abbreviation: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.
Figure 10
Figure 10
Effect of DMDD on the expression of proteins in the TLR4/MyD88/NF-κB pathway. NC: normal control, DN: diabetic nephropathy group, G: gliquidone group (10 mg.kg−1.d−1), H: high dosage of DMDD group (50 mg.kg−1.d−1), M: medium dosage of DMDD group (25 mg.kg−1.d−1), L: low dosage of DMDD group (12.5 mg.kg−1.d−1). A and B: compared with the WT and KO normal controls (P<0.05); a and b: compared with the WT and KO diabetic nephropathy groups (P<0.05); and #: compared with WT mice (P<0.05). Abbreviations: DMDD, 2- dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; WT, wild type; KO, knockout.
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