1. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin.
- Author
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Ichihara, Atsuhiro, Hayashi, Matsuhiko, Kaneshiro, Yuki, Suzuki, Fumiaki, Nakagawa, Tsutomu, Tada, Yuko, Koura, Yukako, Nishiyama, Akira, Okada, Hirokazu, Uddin, M Nasir, Nabi, A H M Nurun, Ishida, Yuichi, Inagami, Tadashi, and Saruta, Takao
- Subjects
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DIABETES complications , *RENIN-angiotensin system , *ANGIOTENSINS , *ANIMAL experimentation , *BIOCHEMISTRY , *COMPARATIVE studies , *DIABETES , *DIABETIC nephropathies , *IMMUNOGLOBULINS , *KIDNEYS , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *MOLECULAR structure , *PEPTIDES , *PROTEIN precursors , *PROTEINS , *RATS , *RENIN , *RESEARCH , *URINE , *ANGIOTENSIN II , *ANGIOTENSIN I , *EVALUATION research , *PREVENTION , *PHYSIOLOGY - Abstract
We found that when a site-specific binding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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