Drug Discovery for Overcoming Chronic Kidney Disease (CKD): New Therapy for CKD by a (Pro)Renin-Receptor-Blocking Decoy Peptide

被引：12
作者：
Ichihara, Atsuhiro [1 ,2 ]
Sakoda, Mariyo [1 ,2 ]
Kurauchi-Mito, Asako [1 ,2 ]
Narita, Tatsuya [1 ,2 ]
Kinouchi, Kenichiro [1 ,2 ]
Itoh, Hiroshi [1 ,2 ]
机构：
[1] Keio Univ, Sch Med, Dept Antiaging Med & Endocrinol, Shinjuku Ku, Tokyo 1608582, Japan
[2] Keio Univ, Sch Med, Dept Internal Med, Shinjuku Ku, Tokyo 1608582, Japan
来源：
JOURNAL OF PHARMACOLOGICAL SCIENCES | 2009年 / 109卷 / 01期
关键词：
angiotensin; diabetes; hypertension; mitogen-activated protein kinase; renin; chronic kidney disease (CKD); PRO RENIN RECEPTOR; (PRO)RENIN RECEPTOR; NONPROTEOLYTIC ACTIVATION; RENIN/PRORENIN RECEPTOR; HANDLE-REGION; HUMAN PRORENIN; NEPHROPATHY; BLOCKADE; RATS;
D O I：
10.1254/jphs.08R07FM
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.
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收藏
页码：20 / 23
页数：4
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