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.
Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. atzichi@sc.itc.keio.ac.jp
Atsuhiro
A
Ichihara
Matsuhiko
M
Hayashi
Yuki
Y
Kaneshiro
Fumiaki
F
Suzuki
Tsutomu
T
Nakagawa
Yuko
Y
Tada
Yukako
Y
Koura
Akira
A
Nishiyama
Hirokazu
H
Okada
M Nasir
MN
Uddin
A H M Nurun
AH
Nabi
Yuichi
Y
Ishida
Tadashi
T
Inagami
Takao
T
Saruta
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