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Therapeutic potential of Keishi-bukuryo-gan on diabetic nephropathy

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Abstract

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Keishi-bukuryo-gan is a Chinese traditional medicine, which is used clinically as a vascular system disordereliminating drug. This review summarizes the effects of Keishi-bukuryo-gan on the occurrence and progression of diabetic nephropathy. To prove its usefulness, we employed two kinds of experimental model animals ; diabetic nephropathy rats induced by subtotal nephrectomy plus streptozotocin injection and spontaneously diabetic WBN/Kob rats. In both animal models, Keishi-bukuryo-gan treatment suppressed increase of urinary protein excretion, which is a prognostically important clinical manifestation for renal functional deterioration in diabetic patients, and preserved renal morphological changes peculiar to diabetic glomerulosclerosis. On the other hand, disorders of the metabolic pathway mediated by persistent hyperglycemia (the glycation reaction, excessive polyol pathway and oxidative stress) were observed. However, oral administration of Keishi-bukuryo-gan normalized the accumulation of advanced glycation endproducts (AGEs), determined by measuring fluorescence, and lipid peroxidation levels in the kidney. Furthermore, by a comparison with aminoguanidine (an AGEs inhibitor), butylated hydroxytoluene (an antioxidant) and captopril (an angiotensin-converting enzyme inhibitor), we confirmed that Keishi-bukuryo-gan prevents diabetic kidney damage from developing and has inhibitory effects against AGEs accumulation and oxidative stress. From these results, we proposed the potential usefulness of Keishi-bukuryo-gan in the treatment of diabetic nephropathy. 桂枝茯苓丸の糖尿病性腎症に対する作用を,2種類のモデルラット(腎摘+STZ,自然発症糖尿病WBN/Kobラット)を用い検討した。いずれのモデルにおいても桂枝茯苓丸投与により,腎機能(尿蛋白排泄量)と病理所見の改善作用が認められ,桂枝茯苓丸が糖尿病性腎症の発症・進展を遅延することが実験的に明らかとなった。一方,慢性的な高血糖状態では酸化ストレス,ポリオール経路,糖化反応の亢進をひき起こし,腎症の進展に関与しているが,これら指標の脂質過酸化,ソルビトール,advanced glycation endproducts(AGEs)を測定した結果,桂枝茯苓丸は脂質過酸化とAGEsに好影響を及ぼしていた。さらに,桂枝茯苓丸の作用を,aminoguanidine(AGEs阻害薬), butylated hydroxytoluene(抗酸化剤),captopril(ACE阻害剤)と比較検討した結果,脂質過酸化とAGEsに対する抑制作用が認められた。また,桂枝茯苓丸の腎保護作用はcaptoprilよりは弱く,amino-guanidineと同程度であった。これらの結果より,桂枝茯苓丸による糖尿病性腎症治療の可能性が示唆された。

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