Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice

Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney ind...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Society of Nephrology 2006-07, Vol.17 (7), p.1950-1961
Main Authors: ICHIHARA, Atsuhiro, SUZUKI, Fumiaki, INAGAMI, Tadashi, NAKAGAWA, Tsutomu, KANESHIRO, Yuki, TAKEMITSU, Tomoko, SAKODA, Mariyo, NURUN NABI, A. H. M, NISHIYAMA, Akira, SUGAYA, Takeshi, HAYASHI, Matsuhiko
Format: Article
Language:English
Subjects:
Angiotensin II - drug effects
Angiotensin II - physiology
Angiotensin-Converting Enzyme Inhibitors - pharmacology
Animals
Associated diseases and complications
Biological and medical sciences
Blood Glucose
Blood Pressure - drug effects
Diabetes Mellitus, Experimental - metabolism
Diabetes. Impaired glucose tolerance
Diabetic Nephropathies - etiology
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - prevention & control
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Glomerulonephritis
Imidazolidines - pharmacology
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinases - physiology
Nephrology. Urinary tract diseases
Nephropathies. Renovascular diseases. Renal failure
Phosphorylation
Receptor, Angiotensin, Type 1 - genetics
Receptors, Cell Surface - antagonists & inhibitors
Renin - blood
Renin-Angiotensin System - genetics
Renin-Angiotensin System - physiology
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2006010029