Highly water-soluble diacetyl chrysin ameliorates diabetes-associated renal fibrosis and retinal microvascular abnormality in db/db mice
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BACKGROUND/OBJECTIVES: Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Oxidative stress and inflammation can be altered by hyperglycemia in diverse tissues, including kidneys and eyes, and play a pivotal role in diabetic complications. Our previous studies showed that the water-insoluble 5,7-dihydroxyflvone chr ysin effectively combats diabetic damages incurred in diabetic kidneys and retinas. The current study employed the newly-synthesized 5.7-di-O-acetylchr ysin, having higher solubility than chr ysin, to compare the effects on diabetes-associated renal fibrosis and abnormal retinal neovascularization. MATERIALS/METHODS: In the in vivo study, db/db mice as animal models of type 2 diabetes were orally administrated 10 mg/kg BW diacetylchr ysin, daily for 10 weeks. RESULTS: Unlike chr ysin, oral administration of 10 mg/kg diacetylchr ysin did not lower the blood glucose level and 24 h urine volume in db/db mice. Nevertheless, the urinar y albumin excretion was markedly reduced. The administration of diacetylchr ysin also diminished the deposition of collagen fibers in diabetic glomeruli and tubules by suppressing the induction of connective tissue growth factor and collagen IV in diabetic kidneys. Supplying diacetylchr ysin enhanced the membrane type-1 matrix metalloproteinase (MMP) expression reduced in diabetic kidneys, while the tissue inhibitor of MMP-2 induction was attenuated in diacetylchr ysin-challenged diabetic kidneys. In addition, supplementing diacetylchr ysin to diabetic mice ameliorated renal injur y due to glomerulosclerosis and tubular interstitial fibrosis. Furthermore, the reduced retinal inductions of Zonula occludens-1 and vascular endothelial cadherin in db/db mice were elevated in the retinal tissues of diacetylchr ysin- treated animals. Oral administration of diacetylchr ysin curtailed the induction of vascular endothelial growth factor (VEGF) and VEGF receptor 2 in db/db mice, ultimately retarding diabetes-associated retinal neovascularization. Additionally, the retinal formation of acellular capillaries with leaky vessels was reduced in diacetylchr ysin-treated db/db mice. CONCLUSION: Diacetylchr ysin may act as a potent pro-health agent for treating renal fibrosis- associated diabetic nephropathy and retinal neovascularization-associated diabetic retinopathy.
Abstract
BACKGROUND/OBJECTIVES: Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Oxidative stress and inflammation can be altered by hyperglycemia in diverse tissues, including kidneys and eyes, and play a pivotal role in diabetic complications. Our previous studies showed that the water-insoluble 5,7-dihydroxyflvone chr ysin effectively combats diabetic damages incurred in diabetic kidneys and retinas. The current study employed the newly-synthesized 5.7-di-O-acetylchr ysin, having higher solubility than chr ysin, to compare the effects on diabetes-associated renal fibrosis and abnormal retinal neovascularization. MATERIALS/METHODS: In the in vivo study, db/db mice as animal models of type 2 diabetes were orally administrated 10 mg/kg BW diacetylchr ysin, daily for 10 weeks. RESULTS: Unlike chr ysin, oral administration of 10 mg/kg diacetylchr ysin did not lower the blood glucose level and 24 h urine volume in db/db mice. Nevertheless, the urinar y albumin excretion was markedly reduced. The administration of diacetylchr ysin also diminished the deposition of collagen fibers in diabetic glomeruli and tubules by suppressing the induction of connective tissue growth factor and collagen IV in diabetic kidneys. Supplying diacetylchr ysin enhanced the membrane type-1 matrix metalloproteinase (MMP) expression reduced in diabetic kidneys, while the tissue inhibitor of MMP-2 induction was attenuated in diacetylchr ysin-challenged diabetic kidneys. In addition, supplementing diacetylchr ysin to diabetic mice ameliorated renal injur y due to glomerulosclerosis and tubular interstitial fibrosis. Furthermore, the reduced retinal inductions of Zonula occludens-1 and vascular endothelial cadherin in db/db mice were elevated in the retinal tissues of diacetylchr ysin- treated animals. Oral administration of diacetylchr ysin curtailed the induction of vascular endothelial growth factor (VEGF) and VEGF receptor 2 in db/db mice, ultimately retarding diabetes-associated retinal neovascularization. Additionally, the retinal formation of acellular capillaries with leaky vessels was reduced in diacetylchr ysin-treated db/db mice. CONCLUSION: Diacetylchr ysin may act as a potent pro-health agent for treating renal fibrosis- associated diabetic nephropathy and retinal neovascularization-associated diabetic retinopathy.
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