Discovery of (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to enzyme and its precursor. Binding of renin and prorenin to the (pro)renin receptor activate two major signaling pathways: the locally generatedangiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin, and the angiotensin II-independent (pro)renin receptor mediated intracellular pathway, involving hypertrophic, hyperplasic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of amino acid sequence of prorenin pro-segment which binds to the receptor and leads to non-proteolytic alteration of prorenin to its active form. A peptide which contains this sequence was found to block the binding of prorenin to its receptor. Its continuous infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade was not effective on 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 provides a maximum benefit under low-renin conditions. Thus, (pro)renin receptor blockade can be a effective therapeutic approach for chronic kidney disease with low renin levels in the plasma.
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