Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin

Atsuhiro Ichihara, Matsuhiko Hayashi, Yuki Kaneshiro, Fumiaki Suzuki, Tsutomu Nakagawa, Yuko Tada, Yukako Koura, Akira Nishiyama, Hirokazu Okada, M. Nasir Uddin, A. H M Nurun Nabi, Yuichi Ishida, Tadashi Inagami, Takao Saruta

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362 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1128-1135
Number of pages8
JournalJournal of Clinical Investigation
Volume114
Issue number8
DOIs
Publication statusPublished - 2004 Oct

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Diabetic Nephropathies
Renin
Peptides
Kidney
Streptozocin
Carrier Proteins
Angiotensinogen
Hyperglycemia
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

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Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. / 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; Saruta, Takao.

In: Journal of Clinical Investigation, Vol. 114, No. 8, 10.2004, p. 1128-1135.

Research output: Contribution to journalArticle

Ichihara, A, Hayashi, M, Kaneshiro, Y, Suzuki, F, Nakagawa, T, Tada, Y, Koura, Y, Nishiyama, A, Okada, H, Uddin, MN, Nabi, AHMN, Ishida, Y, Inagami, T & Saruta, T 2004, 'Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin', Journal of Clinical Investigation, vol. 114, no. 8, pp. 1128-1135. https://doi.org/10.1172/JCI200421398
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 ; Saruta, Takao. / Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 8. pp. 1128-1135.
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AU - Suzuki, Fumiaki

AU - Nakagawa, Tsutomu

AU - Tada, Yuko

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AU - Nishiyama, Akira

AU - Okada, Hirokazu

AU - Uddin, M. Nasir

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AU - Ishida, Yuichi

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AU - Saruta, Takao

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