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薬理と治療
Abstract
Diabetic nephropathy is one of the main causes of death in diabetic patients. Hyperglycemiaand hypertension are risk factors for diabetic nephropathy. Recently it has been proposedthat hypertriglyceridemia contributes to diabetic nephropathy. In JDCS(Japan Diabetes ComplicationsStudy)and UKPDS(UK Prospective Diabetes Study)74, hypertriglyceridemia wasdetected as one of the risk factors for diabetic nephropathy. In FIELD(Fenofibrate InterventionEvent Lowering in Diabetes)study, fenofibrate therapy reduced plasma level of triglyceride(TG), and prevented and improved diabetic nephropathy in type 2 diabetic patients.Increased remnant lipoproteins underlie hypertriglyceridemia. We first found that increasedremnant lipoproteins contribute to diabetic nephropathy. It is proposed that remnant lipoproteinsare taken up by mesangial cells, and then cause renal damage. Diabetic nephropathy ischaracterized by the accumulation of extracellular matrix protein(type IV collagen)in theglomerular mesangium and expansion of the mesangial matrix, resulting in glomerulosclerosis.TGF−β stimulates type IV collagen protein synthesis. Fibrate, which is a ligand forPPARα, reduces plasma levels of TG and remnant lipoproteins and possibly may protect andimprove nephropathy thorough PPARα.In the present study we examined the effect of bezafibrate on TGF−β and type IV collagenexpression in human mesangial cells(HMCs)loaded with remnant lipoproteins in themedium.Remnant lipoproteins were isolated from plasma of a patient with type 2 diabetes andtypeIII hyperlipoproteinemia by ultracentrifugal method. HMCs loaded with remnant lipoproteiswere incubated for up to 24 h with bezafibrate at the concentration of 0, 3×10−6, 3×10−5 and 3×10−4 mol/L. To evaluate the expression of TGF−β mRNA and type IV collagenmRNA in mesangial cells, RT−PCR procedure was performed.Remnant lipoproteins significantly(p<0.001)stimulated the expression of TGF−β mRNAand type IV collagen mRNA in HMCs. Bezafibrate significantly(p<0.001 or p<0.01)suppressesthe expression of TGF−β mRNA in HMCs loaded with remnant lipoproteins in adose−dependent manner. Bezafibrate significantly (p<0.001 or p<0.05) suppresses theexpression of type IV collagen mRNA in HMCs loaded with remnant lipoproteins in a dosedependentmanner.Remnant lipoproteins stimulate the expression of TGF−β and type IV collagen inHMCs. It is concluded that remnant lipoproteins play an important role in the developmentand progression of diabetic nephropathy through TGF−β and type IV collagen. In addition,bezafibrate suppresses the expression of TGF−β and type IV collagen in HMCs loaded withremnant lipoproteins. It is suggested that bezafibrate is effective to protect and improve diabeticnephropathy.(Jpn Pharmacol Ther 2009;37:117−22)KEY WORDS Bezafibrate, TGF−β, Type IV collagen, Remnant lipoproteins, Mesangialcells, Diabetic nephropathy
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