structure of prorenin molecule

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In 2005, using streptozotocin-induced diabetic angiotensin-II-type-1-receptor-deficient-mice, we provided the evidence that angiotensin II-independent pathway caused by binding of human prorenin to human (pro)renin receptor significantly contributes to the development and progression of diabetic nephropathy. In 2006, using human cultured vascular smooth muscle cells, we observed the localization of human (pro)renin receptor in the cytosol close to nucleus and its transposition into the nucleus by the load of prorenin. In addition, rat prorenin was capable of binding to human (pro)renin receptor and thus stimulating the receptor-dependent intracellular signals but was not activated by binding to human (pro)renin receptor. In human vascular smooth muscle cells, human prorenin stimulated the MAP kinase pathways, leading to cell proliferation, through binding to human (pro)renin receptor independently of angiotensin II. In 2007, we developed human-(pro)renin-receptor-transgenic rats which have no enhanced tissue renin-angiotensin system because rat prorenin is incapable of being activated by binding to human (pro)renin receptor. However, the human-(pro)renin-receptor-transgenic rats had an enhanced (pro)renin receptor-dependent intracellular signaling pathways, and slowly progressive nephropathy, that is glomerulosclerosis with proteinuria developed in the transgenic rats. The development of nephropathy occurred in the transgenic rats was caused by the receptor-dependent MAP kinase pathways and was independent of blood pressure or renal angiotensin II levels. Thus, the human-(pro)renin-receptor-transgenic rats was thought to be useful for studying the signals of human(pro)renin receptor in vivo.