Study for model of diabetic nephropathy and prevention of disease progress

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Diabetic nephropathy is one of the most important diseases for cause of endstage kidney disease. The pathogenesis and treatment of the disease are critical for medical and social problems. Diabetic complications are mediated by advanced glycation endproducts (AGE) which produced by long-term reaction between proteins and high glucose condition. This study was designed to establish the model of diabetic nephropathy and to study the mechanism and the prevention of disease progress. We analyzed knockout mice for apolipoprotein E that developed the progressive glomerulosclerosis in association with glomerular hypertrophy. Mesangial cells had a low affinity receptor for AGE (RAGE) and increased the synthesis of extracellular matrix including type IV collagen. This reaction was mediated by specific DNA binding protein for promoter of type IV collagen (Alp145), which had multifunctions including DNA replication factor C and DNA binding proteins for promoter of angiotensinogen. The expression … More of Alp145 was correlated with glomerular sclerosis and cell proliferation in vivo model. Furthermore, we applied the hammerhead ribozyme for targeting RAGE and established a stable cell line that produced RAGE-specific ribozyme. The induction of type IV mRNA by AGE on mesangial cell was inhibited by RAGE-specific ribozyme. Heat shock protein 47 (HSP47) is a collagen-specific chaperone that has a major role during the biosynthesis and secretion of procollagen molecules. The expression of HSP47 increased in parallel with the expression of collagens during the progression of glomerulosclerosis in renal ablation rats. The administration of antisense oligonucleotides against HSP47 at the induction of anti-thy-1 glomerulonephritis markedly suppressed the increased production of collagens and attenuated the histological manifestations of desease. This study provides to establish the model for typical glomerulosclerosis, to determine the mechanisms of disease progression, and to further develop new strategy for prevention of disease progression. Less