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

J Clin Invest. 2004 Oct;114(8):1128-35. doi: 10.1172/JCI21398.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism
  • Angiotensin II / metabolism
  • Angiotensinogen / metabolism
  • Animals
  • Antibodies / metabolism
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control
  • Enzyme Activation
  • Kidney / cytology
  • Kidney / metabolism*
  • Kidney / pathology
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Conformation
  • Protein Precursors / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Renin / chemistry*
  • Renin / metabolism*
  • Renin-Angiotensin System / physiology
  • Urine / chemistry


  • Antibodies
  • Peptides
  • Protein Precursors
  • Angiotensinogen
  • Angiotensin II
  • Angiotensin I
  • Renin