Drug discovery for overcoming chronic kidney disease (CKD): new therapy for CKD by a (pro)renin-receptor-blocking decoy peptide.
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.
Ichihara
Atsuhiro
A
Department of Anti-Aging Medicine & Endocrinology, Keio University School of Medicine, Tokyo, Japan. atzichi@sc.itc.keio.ac.jp
Sakoda
Mariyo
M
Kurauchi-Mito
Asako
A
Narita
Tatsuya
T
Kinouchi
Kenichiro
K
Itoh
Hiroshi
H
D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D008954:Models, Biological; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D000093342:Prorenin Receptor
D010455:Peptides; D011956:Receptors, Cell Surface; D000093342:Prorenin Receptor