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Renoprotective Properties of Angiotensin Receptor Blockers beyond Blood Pressure Lowering

Yuko Izuhara^*, Masaomi Nangaku, Reiko Inagi^*, Naoto Tominaga^*, Toru Aizawa^*, Kiyoshi Kurokawa^*, Charles van Ypersele de Strihou and Toshio Miyata^*

^* Institute of Medical Sciences and Division of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; and Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium

Address correspondence to: Dr. Toshio Miyata, Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Phone: +81-463-93-1936; Fax: +81-463-93-1938; E-mail: t-miyata{at}is.icc.u-tokai.ac.jp

Received for publication May 18, 2005. Accepted for publication September 8, 2005.

Clinical studies have demonstrated that some antihypertensive agents provide renoprotection independent of BP lowering. Recent in vitro and in vivo studies evaluated the mechanisms involved in this protection. First, the in vitro effects of several angiotensin II type 1 receptor blockers (ARB), calcium channel blockers (CCB), and blockers (BB) on various mediators were compared: Formation of pentosidine (an advanced glycation end product), hydroxyl radical-induced formation of o-tyrosine, and transition metals–induced oxidation of ascorbic acid (the Fenton reaction). All of the six tested ARB but neither the six CCB nor the nine BB inhibited pentosidine formation. ARB, as well as BB but not CCB, inhibited hydroxyl radicals–mediated o-tyrosine formation. ARB but neither BB nor CCB inhibited efficiently transition metals–catalyzed oxidation of ascorbic acid. Second, the in vivo consequences for the kidney of these various in vitro effects were evaluated. Hypertensive, type 2 diabetic rats with nephropathy, SHR/NDmcr-cp, were given for 20 wk either olmesartan (ARB) or nifedipine (CCB), or atenolol (BB). Despite similar BP reduction, only ARB significantly reduced proteinuria and prevented glomerular and tubulointerstitial damage (mesangial activation, podocyte injury, tubulointerstitial injury, and inflammatory cell infiltration). It is interesting that only ARB prevented abnormal iron deposition in the interstitium, corrected chronic hypoxia, reduced expressions of heme oxygenase and p47phox (a subunit of NADPHoxidase), and inhibited pentosidine formation (which correlates well with proteinuria). These observations confirm unique renoprotective properties of ARB, independent of BP lowering but related to decreased oxidative stress (hydroxyl radicals scavenging and inhibition of the Fenton reaction), correction of chronic hypoxia, and inhibition of advanced glycation end product formation and of abnormal iron deposition. These benefits of ARB may contribute to the renoprotection observed beyond BP lowering.

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