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 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.
Ichihara
Atsuhiro
A
Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan. atzichi@sc.itc.keio.ac.jp
Suzuki
Fumiaki
F
Nakagawa
Tsutomu
T
Kaneshiro
Yuki
Y
Takemitsu
Tomoko
T
Sakoda
Mariyo
M
Nabi
A H M Nurun
AH
Nishiyama
Akira
A
Sugaya
Takeshi
T
Hayashi
Matsuhiko
M
Inagami
Tadashi
T
D000804:Angiotensin II / Q000187:drug effects / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D048289:Imidazolidines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D000093342:Prorenin Receptor
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D048289:Imidazolidines; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D000804:Angiotensin II; C065166:imidapril; D020928:Mitogen-Activated Protein Kinases; D012083:Renin; D000093342:Prorenin Receptor