(Pro)Renin Receptor Peptide Inhibitor “Handle-Region” Peptide Does Not Affect Hypertensive Nephrosclerosis in Goldblatt Rats

Abstract

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the “handle-region” peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats. Vehicle-treated 2K1C rats were compared with HRP-treated 2K1C rats (3.5 μg/kg per day) and sham-operated controls. Vehicle-treated 2K1C rats developed hypertension (186±17 mm Hg), cardiac hypertrophy (3.16±0.16 mg/g), renal inflammation, fibrosis, vascular, and tubular damage. Chronic HRP treatment did not affect blood pressure (194±15 mm Hg), cardiac hypertrophy (2.97±0.11 mg/g), or renal damage. Furthermore, we investigated the renal renin and (P)RR expression. The clipped kidney of 2K1C and HRP-treated 2K1C rats showed a higher renin expression and juxtaglomerular index compared with sham-operated kidneys. The unclipped kidney showed suppressed renin expression. In contrast, (P)RR mRNA expression was not altered in any group. Plasma renin activity and aldosterone were increased in 2K1C rats compared with sham controls. HRP-treated 2K1C rats tended to lower plasma renin activity but showed similar aldosterone levels as vehicle-treated 2K1C rats. Our results indicate that blockade of the (P)RR with HRP does not improve target organ damage in renovascular hypertensive rats.