Elsevier

Peptides

Volume 30, Issue 8, August 2009, Pages 1575-1585
Peptides

Review
The renin–angiotensin system, adrenomedullins and urotensin II in the kidney: Possible renoprotection via the kidney peptide systems

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Abstract

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin–angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease.

Introduction

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney function [37], [104], [120], [130], [132], [138]. The kidney synthesizes numerous biologically active peptides and expresses receptors for them. The classical example of the biologically active peptides in the kidney is the renin–angiotensin system (RAS) [22], [95], [138]. Angiotensin II (Ang II) plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation and reactive-oxygen generating activity, and the drugs to block the intrarenal RAS are now the major treatment for chronic kidney disease [47], [95], [138]. Endothelins, neuropeptide Y (NPY) and urotensin II (UII) are representative vasoconstrictor peptides that are expressed in the kidney, in addition to the RAS [114], [130]. Vasodilator peptides, such as natriuretic peptides (atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP)), adrenomedullins (AMs) and urocortins are also expressed in the kidney [59], [111], [117], [131], [132]. Moreover, neuropeptides without remarkable vascular actions, such as orexin-A, are expressed in the kidney [110].

The kidney peptides that antagonize the intrarenal RAS may play protective roles against various stresses, such as oxidative stress [70] (Table 1). For example, AM and AM2 have been shown to have renoprotective actions [23], [70]. On the other hand, UII may promote the renal dysfunction in chronic renal disease together with the renal RAS [104], although the exact pathophysiological roles of UII in chronic kidney disease are still controversial. Thus, AMs and UII may be novel targets to develop therapeutic strategies against chronic kidney disease. We will therefore discuss the novel aspects of the RAS (renin inhibitor and (pro)renin receptor), AMs and UII in the kidney in this review article.

Section snippets

Renin–angiotensin system (RAS)

Renin is synthesized primarily by the juxtaglomerular apparatus [30], [138], angiotensinogen mainly secreted by the liver is converted to angiotensin I (Ang I) in the circulation by the enzymatic action of renin, and then further converted to Ang II by angiotensin-converting enzyme (ACE) (Fig. 1). Ang II has various functions in the brain, and cardiovascular, renal, endocrine and other organs, such as vasoconstriction, aldosterone release, cell proliferation and hypertrophy, stimulation of

Adrenomedullins (AMs)

Adrenomedullin (AM) is a 52 amino acid peptide originally isolated from pheochromocytoma [41], and belongs to the calcitonin/calcitonin gene-related peptide (CGRP) family, which includes calcitonin, CGRP, and amylin. AM has a potent vasodilator action and other various biological actions, such as actions on cell proliferation, hormone secretion, an anti-apoptotic action, neurotransmitter actions and an anti-bacterial action [20], [109]. There are at least five genes for adrenomedullin family

Urotensin II (UII) and urotensin II-related peptide (URP)

Urotensins are originally fish peptide hormones which were isolated from the caudal neurosecretory system of teleost fish, urophysis [33], [48], [86]. Urotensin I (UI) is a corticotropin-releasing factor (CRF)-like peptide [33], [48] and the mammalian homologs are urocortins (urocortin1, urocortin2 and urocortin3). UII was considered to be a fish somatostatin-like peptide with a cyclic structure, and has been identified in mammals including human [3], [18] (Fig. 3). Human UII was found to be an

Relations among the RAS, AMs and UII

Relations and/or cross-talks among the RAS, AMs and UII have not been clarified in the (patho)physiology of kidney in detail yet. However, there has been accumulating evidence which suggests the interaction among the RAS, AMs and UII in cardiovascular physiology and diseases.

AM expression has been shown to be induced by Ang II, and AM antagonizes various Ang II-induced effects. Ang II stimulates AM production by left ventricle of heart in vivo [79] and by cultured human aortic endothelial cells

Conclusion

The activation of the RAS promotes the progression of chronic kidney disease such as diabetic nephropathy, and therefore, ACE inhibitors and AT1 receptor antagonists are widely used for the treatment for chronic kidney disease. A renin inhibitor, aliskiren, has been shown to be clinically renoprotective in patients with diabetic nephropathy. (P)RR, a recently identified receptor for prorenin and renin, may be a novel target to suppress the RAS and to develop the effective therapeutic strategies

Acknowledgments

The authors are very grateful to our following collaborators: Dr. Osamu Murakami, Dr. Fumitoshi Satoh, Prof. Sadayoshi Ito, Prof. Takashi Suzuki, and Prof. Hironobu Sasano (Departments of Medicine and Pathology, Tohoku University Graduate School of Medicine, Sendai Japan). This study was supported partly by Tohoku University 21st COE Program Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation (CRESCENDO), by Grants-in-aid for Scientific Research

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    This paper was partly presented at the International Symposium of Biologically Active Peptides: Peptide Diversity (The 1st Japan Branch Meeting of the International Neuropeptide Society) held in Sendai, Japan on 31 August and 1 September 2008.

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