Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin
Atsuhiro Ichihara, … , Tadashi Inagami, Takao Saruta
Atsuhiro Ichihara, … , Tadashi Inagami, Takao Saruta
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1128-1135. https://doi.org/10.1172/JCI21398.
View: Text | PDF
Article Metabolism

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

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.

Authors

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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of the development of diabetic nephropathy by the HRP of pror...
Inhibition of the development of diabetic nephropathy by the HRP of prorenin. (A) PAS-stained kidney sections. The photomicrographs show the development and progression of diabetic glomerulosclerosis at 20 weeks of age and later in DM rats. HRP inhibited the development of diabetic glomerulosclerosis in diabetic rats. Scale bars: 50 μm. (B) Glomerulosclerosis index of the kidneys in C rats (white bars, n = 6), C + HRP rats (light gray bars, n = 6), DM rats (black bars, n = 6), and DM + HRP rats (dark gray bars, n = 6). The graph shows an increase in glomerulosclerosis index at 20 weeks of age and later in DM rats and inhibition of the increase by HRP treatment. *P < 0.05 for DM rats versus the other 3 groups; P < 0.05 for 28 versus 20 weeks of age. (C) Immunohistochemistry of type IV collagen. The photomicrographs show increased glomerular type IV collagen at 20 weeks of age and later in DM rats. HRP inhibited the increase in glomerular type IV collagen in the diabetic rats. Scale bars: 50 μm. (D) Quantitative analysis (folds versus C rats) of type IV collagen–positive areas in glomeruli. The graph shows an increase in type IV collagen–positive area in the glomeruli of DM rats at 28 weeks of age and inhibition of the increase by HRP treatment. *P < 0.05 versus C rats.