Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy

in Journal of Endocrinology
Correspondence should be addressed to C H Chung: cchung@yonsei.ac.kr
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Dibenzoylmethane (DBM) is a beta-diketone analog of curcumin. Numerous studies have shown the beneficial effects of curcumin on diabetes, obesity and diabetic complications including diabetic nephropathy. Recently, we investigated the beneficial metabolic effects of DBM on high-fat diet-induced obesity. However, the effects and mechanisms of action of DBM in the kidney are currently unknown. To investigate the renoprotective effects of DBM in type 2 diabetes, we administered DBM (100 mg/kg) orally for 12 weeks to high-fat diet-induced diabetic model mice. We used mouse renal mesangial (MES13) and macrophage (RAW 264.7) cells to examine the mechanism of action of DBM (20 μM). After DBM treatment, the albumin-to-creatinine ratio was significantly decreased compared to that of the high-fat-diet group. Moreover, damaged renal ultra-structures and functions including increased glomerular volume, glomerular basement membrane thickness and inflammatory signals were ameliorated after DBM treatment. Stimulation of MES13 and RAW264.7 cells by palmitate or high-dose glucose with lipopolysaccharides increased inflammatory signals and macrophage migration. However, these changes were reversed by DBM treatment. In addition, DBM inhibited NADPH oxidase 2 and 4 expression and oxidative DNA damage. Collectively, these data suggested that DBM prevented diabetes-induced renal injury through its anti-inflammatory and antioxidant effects.

 

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    Chemical structures of curcumin and dibenzoylmethane (DBM).

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    Changes in number of high-fat diet (HFD)-induced crown-like structures in white adipose tissue and levels of renal triglycerides caused by dibenzoylmethane (DBM) administration. (A) H&E staining of white adipose tissue. (B) Measurement of adipocyte sizes. (C) Renal TG levels were measured by converting TG to glycerol. (D) Renal p-AMPK and p-ACC levels were analyzed using western blotting. Arrow, crown-like structures; DBM, HFD plus dibenzoylmethane; H&E, hematoxylin and eosin; HFD, high-fat diet group; ND, normal diet group; TG, triglycerides; WAT, white adipose tissue. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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    Effects of dibenzoylmethane (DBM) on high-fat diet (HFD)-induced diabetic nephropathy (DN). (A) Albumin-to-creatinine ratio (ACR) was measured in urine over a 24-h collection period. (B) Glomerular expansion was analyzed using H&E staining of renal glomeruli and renal ultrastructure was analyzed using transmission electron microscopy (TEM). Changes in glomerular volumes (C), slit pore numbers (D and E) and GBM thickness (D and F) were determined. ACR, albumin/creatinine ratio; DBM, HFD plus dibenzoylmethane; GBM, glomerular basement membrane; HFD, high-fat diet group; ND, normal diet group. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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    Effects of dibenzoylmethane (DBM) on macrophage infiltration and inflammatory signals in the kidney. Renal nephrin, CD68, and arginase 2 levels were analyzed using western blotting and quantified (A). Renal MCP1 mRNA level was quantified using qPCR (B). Immunohistochemical staining of the MCP1 (C), F4/80 and CD11c (D). p-AMPK and inflammatory signals, including p-p38 and p-IKKβ, were detected by western blotting in the kidney and quantified (E). AMPK, AMP-activated protein kinase; DBM, HFD plus dibenzoylmethane; HFD, high-fat diet group; ND, normal diet group; qPCR, quantitative polymerase chain reaction. aP < 0.05 compared with the ND group; bP < 0.05 compared with HFD group. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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    AMP-activated protein kinase (AMPK) activation by dibenzoylmethane (DBM) and curcumin. (A) Comparison of effects of curcumin and DBM on AMPK activation in NRK-52E cells. (B) DBM dose-dependently activated p-AMPK. (C) Changes in p-AMPK expression induced by high-glucose (HG), compound C, or both in the presence or absence of DBM. (D) PA-induced inflammatory signals (IkB and p-NFkB p65) in MES-13 cells caused by DBM treatment. (E) LPS-induced macrophage migration was affected by DBM treatment. (F) p-IKK, IkB, and p-NFkB p65 levels were changed by CM and changes were reversed by DBM treatment. CM, Raw 264.7 cultured medium with LPS; DBM, dibenzoylmethane; HG, high-glucose, 30 mM glucose in DMEM; LG, low-glucose, 5.5 mM glucose in DMEM; LPS, lipopolysaccharide; PA, palmitate. aP < 0.05 compared with LG; bP < 0.05 compared with HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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    Antioxidant effects of dibenzoylmethane (DBM). (A) Oxidative DNA damage marker, 8-OHdG, showed staining in glomeruli. (B) Changes in Nrf2/HO-1 expression by DBM in HG and LPS-stimulated MES-13 cells. (C and D) NOX2 and NOX4 protein and mRNA expressions change by DBM treatment in HG with LPS-stimulated MES-13. 8-OHdG, 8-hydroxy-2′-deoxyguanosine; DBM, dibenzoylmethane; HG, high-glucose, 30 mM glucose in DMEM; LG, low-glucose, 5.5 mM glucose in DMEM; LPS, lipopolysaccharide. aP < 0.05 compared with LG; bP < 0.05 compared with HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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    Schematic presentation of effects of dibenzoylmethane (DBM) on diabetic nephropathy (DN) in mouse model of high-fat diet (HFD)-induced diabetes. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0206.

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