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Updated: Jun 22, 2026
A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Renin, prorenin and the kidney: a new chapter in an old saga
Atsuhiro Ichihara1, Mariyo Sakoda, Asako Kurauchi-Mito
1Departments of Anti-Aging Medicine & Endocrinology, Keio University School of Medicine, Shinjuku-ku, Tokyo - Japan. atzichi@sc.itc.keio.ac.jp
Abstract:
The binding of prorenin to the (pro)renin receptor triggers 2 major pathways: a nonproteolytic conformational change in prorenin to its active form (angiotensin II-dependent pathway) and an intracellular pathway via the (pro)renin receptor itself (angiotensin II-independent pathway). In diabetic animals, an increased plasma prorenin level not only causes the generation of angiotensin II via the angiotensin II-dependent pathway, it also stimulates the transliteration receptors own intracellular signaling pathway in a manner that is independent of the generated angiotensin II. Thus, the administration of a "handle" region peptide (HRP), which acts as a decoy peptide and competitively inhibits the binding of prorenin to the (pro)renin receptor, has a beneficial effect in the kidneys of diabetic animals with low plasma renin levels. However, the benefits of HRP are slightly reduced in animal models of essential hypertension with relatively high plasma renin levels, and these benefits disappear altogether in animal models of hypertension with extremely high plasma renin levels. Thus, in the kidneys of animal models of diabetes and/or hypertension, both renin and prorenin competitively bind to the (pro)renin receptor and contribute to the pathophysiology of nephropathy. Consequently, renin, prorenin and the (pro) renin receptor may be important therapeutic targets for the prevention and regression of nephropathy in patients with diabetes and/or hypertension.
Insights
Handle region peptide (HRP) administration benefits diabetic kidneys by blocking prorenin binding. However, its efficacy decreases with higher renin levels in hypertension models, suggesting renin-angiotensin system components are key targets for nephropathy.
Area of Science:
- Biochemistry and Molecular Biology
- Nephrology
- Endocrinology
Background:
- The (pro)renin receptor (PRR) mediates prorenin's effects through both angiotensin II-dependent and independent pathways.
- Elevated plasma prorenin in diabetes stimulates PRR signaling independently of angiotensin II.
- Renin and prorenin binding to PRR contributes to diabetic and hypertensive nephropathy.
Purpose of the Study:
- To investigate the therapeutic potential of a handle region peptide (HRP) in mitigating kidney damage.
- To evaluate the efficacy of HRP in animal models of diabetes and hypertension.
- To elucidate the role of renin-prorenin-PRR axis in nephropathy pathogenesis.
Main Methods:
- Administration of handle region peptide (HRP) as a decoy to inhibit prorenin-PRR binding.
- Utilized animal models of diabetes and essential hypertension with varying plasma renin levels.
- Assessed the beneficial effects of HRP on kidney pathology.
Main Results:
- HRP demonstrated beneficial effects in the kidneys of diabetic animals with low plasma renin.
- HRP's benefits were reduced in hypertensive models with higher plasma renin levels.
- HRP efficacy was lost in models with extremely high plasma renin levels.
Conclusions:
- Both renin and prorenin competitively bind to the (pro)renin receptor, contributing to nephropathy.
- The handle region peptide (HRP) shows therapeutic promise, particularly in diabetic nephropathy.
- Targeting the renin-prorenin-PRR axis offers a potential strategy for preventing and reversing nephropathy.
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