ReviewThe renin–angiotensin system, adrenomedullins and urotensin II in the kidney: Possible renoprotection via the kidney peptide systems☆
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
References (147)
- et al.
Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice
Kidney Int
(2009) - et al.
Human adrenomedullin gene delivery protects against cardiovascular remodeling and renal injury
Peptides
(2001) - et al.
Structure–activity relationships and structural conformation of a novel urotensin II-related peptide
Peptides
(2004) - et al.
Involvement of reactive oxygen species in urotensin II-induced proliferation of cardiac fibroblasts
Eur J Pharmacol
(2008) - et al.
Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway
Kidney Int
(1997) - et al.
Pro-A-type natriuretic peptide and pro-adrenomedullin predict progression of chronic kidney disease: the MMKD Study
Kidney Int
(2009) A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides
Peptides
(2001)- et al.
Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension
J Hepatol
(2002) - et al.
Expression and regulation of adrenomedullin in renal glomerular podocytes
Biochem Biophys Res Commun
(2005) - et al.
The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats
Kidney Int
(2004)
Increased expression of urotensin II, urotensin II-related peptide and urotensin II receptor mRNAs in the cardiovascular organs of hypertensive rats: comparison with endothelin-1
Peptides
Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms
Kidney Int
Isolation and amino acid sequence of urotensin I, a vasoactive and ACTH-releasing neuropeptide, from the carp (Cyprinus carpio) urophysis
Peptides
Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma
Biochem Biophys Res Commun
Decreased synthesis of glomerular adrenomedullin in patients with IgA nephropathy
J Lab Clin Med
A quantitative study to assess synergistic interactions between urotensin II and angiotensin II
Eur J Pharmacol
Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy
Am J Kidney Dis
Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on different sodium intakes
Kidney Int
Urotensin II and biomarkers of endothelial activation and atherosclerosis in end-stage renal disease
Am J Hypertens
Expression of adrenomedullin2/intermedin in human brain, heart, and kidney
Peptides
Increased expression of urotensin II-related peptide and its receptor in kidney with hypertension or renal failure
Peptides
Role of adrenomedullin and its receptor system in renal pathophysiology
Peptides
Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis
Kidney Int
Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy
Biochem Biophys Res Commun
Induction of adrenomedullin by hypoxia and cobalt chloride in human colorectal carcinoma cells
Biochem Biophys Res Commun
Increased gene expression of urotensin II-related peptide in the hearts of rats with congestive heart failure
Peptides
Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen
Kidney Int
Identification of a novel adrenomedullin gene family in teleost fish
Biochem Biophys Res Commun
Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial
Lancet
Targeted overexpression of the human urotensin receptor transgene in smooth muscle cells: Effect of UT antagonism in ApoE knockout mice fed with Western diet
Atherosclerosis
Adrenomedullin decreases extracellular signal-regulated kinase activity through an increase in protein phosphatase-2A activity in mesangial cells
Eur J Pharmacol
Cellular and molecular actions of adrenomedullin in glomerular mesangial cells
Peptides
Adrenomedullin reduces mesangial cell number and glomerular inflammation in experimental mesangioproliferative glomerulonephritis
Kidney Int
Cardiovascular effects of native and non-native urotensin II and urotensin II-related peptide on rat and salmon hearts
Peptides
Biological properties and functional determinants of the urotensin II receptor
Peptides
Urotensin II is an inverse predictor of death and fatal cardiovascular events in chronic kidney disease
Kidney Int
Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes
J Biol Chem
The paradox of the renin–angiotensin system in chronic renal disease
Kidney Int
Adrenomedullin antagonizes angiotensin II-stimulated proliferation of human aortic smooth muscle cells
Peptides
Adrenomedullin inhibits angiotensin II-induced contraction in human aortic smooth muscle cells
Regul Pept
Enhanced renal sensitivity of the spontaneously hypertensive rat to urotensin II
Am J Physiol Renal Physiol
Renal haemodynamic and tubular actions of urotensin II in the rat
J Endocrinol
Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14
Nature
Oxidative stress increases adrenomedullin mRNA levels in cultured rat vascular smooth muscle cells
Hypertens Res
Urotensin-II levels in children with minimal change nephrotic syndrome
Pediatr Nephrol
Urotensin II evokes potent vasoconstriction in humans in vivo
Br J Pharmacol
Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries
Br J Pharmacol
Chronic salt loading upregulates expression of adrenomedullin and its receptors in adrenal glands and kidneys of the rat
Hypertension
Hemodynamic, hormonal, and renal actions of adrenomedullin-2 in normal conscious sheep
Endocrinology
Plasma concentration of urotensin II is raised in hypertension
J Hypertens
Cited by (0)
- ☆
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.