Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin.
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.
Ichihara
Atsuhiro
A
Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. atzichi@sc.itc.keio.ac.jp
Hayashi
Matsuhiko
M
Kaneshiro
Yuki
Y
Suzuki
Fumiaki
F
Nakagawa
Tsutomu
T
Tada
Yuko
Y
Koura
Yukako
Y
Nishiyama
Akira
A
Okada
Hirokazu
H
Uddin
M Nasir
MN
Nabi
A H M Nurun
AH
Ishida
Yuichi
Y
Inagami
Tadashi
T
Saruta
Takao
T
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004789:Enzyme Activation; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012083:Renin / Q000737:chemistry* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D014556:Urine / Q000737:chemistry
D000906:Antibodies; D010455:Peptides; D011498:Protein Precursors; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D012083:Renin