Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic Toshio Nishikimi a, * , Xin Wang a , Kazumi Akimoto b , Kazuyoshi Tadokoro a , Yosuke Mori a , Yayoi Ishikawa a , Kimihiko Ishimura a , Fumiki Yoshihara c , Naoto Minamino c , Kenji Kangawa c , Hiroaki Matsuoka a a Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan b Laboratory of Molecular and Cellular Biology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan c National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan Received 13 April 2004; received in revised form 19 June 2004; accepted 1 July 2004 Available online 6 August 2004 Abstract Objective: We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. Method: We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic- treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. Results: SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM- mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. Conclusion: Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP. D 2004 Elsevier B.V. All rights reserved. Keywords: Adrenomedullin; Hypertension; Renal cortex; Renal medulla; Renal impairment 1. Introduction The 52-amino-acid peptide adrenomedullin (AM), dis- covered in human pheochromocytoma tissues [1], has potent hypotensive activity in a variety of species [2,3]. In addition to its vascular effects, AM has natriuretic and diuretic actions [2,3]. The AM gene and its peptide are distributed in a broad range of tissues, including the kidneys [1,4,5] The AM gene and specific binding sites for AM peptide are expressed in the kidney [6]. Plasma levels of AM are increased in a variety of disorders, including hypertension [7], renal impairment [7,8], and congestive heart failure [9,10]. Thus, AM may be involved in the pathophysiology of cardiovascular disease. However, the pathophysiological implications of AM in renal impairment associated with malignant hypertension are not fully understood. Considerable colocalization between the expression of AM peptide and AM mRNA and the expression of AM receptors in the kidney suggests that this peptide may act as an autocrine or paracrine factor (or as both) and influence 0167-0115/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2004.07.003 * Corresponding author. Tel.: +81-282-87-2149; fax: +81-282-86- 1596. E-mail address: nishikim@dokkyomed.ac.jp (T. Nishikimi). Regulatory Peptides 124 (2005) 89 – 98 www.elsevier.com/locate/regpep