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Regression of Nephropathy Developed in Diabetes by (Pro)renin Receptor Blockade

Hidena Takahashi^*, Atsuhiro Ichihara^*, Yuki Kaneshiro^*, Kenta Inomata^*, Mariyo Sakoda^*, Tomoko Takemitsu^*, Akira Nishiyama and Hiroshi Itoh^*

^* Internal Medicine, Keio University School of Medicine, Tokyo, and Pharmacology, Kagawa University School of Medicine, Kagawa, Japan

Correspondence: Dr. Atsuhiro Ichihara, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Phone: +81-3-5363-3796; Fax: +81-3-3359-2745; E-mail: atzichi{at}sc.itc.keio.ac.jp

Received for publication August 3, 2006. Accepted for publication April 10, 2007.

Activation of prorenin by (pro)renin receptor stimulates the tissue renin-angiotensin system and plays a significant role in the development of nephropathy in diabetic animals. This study examined whether (pro)renin receptor blockade inhibits the progression of nephropathy that has already developed in diabetic rats. Seventeen-week-old heminephrectomized streptozotocin-induced diabetic rats with an increased urinary protein excretion and a significant glomerulosclerosis had been treated for 12 wk with the (pro)renin receptor blocker (PRRB), angiotensin-converting enzyme inhibitor (ACEi), or vehicle peptide by using subcutaneously implanted osmotic minipumps. At the end of observation, in diabetic rats that were treated with vehicle, urinary protein excretion was progressively increased and a significant progression of glomerulosclerosis was observed. In diabetic rats that were treated with PRRB, however, no further increase in urinary protein excretion or glomerulosclerosis was observed, but 12-wk treatment with ACEi only attenuated further increases in urinary protein excretion and glomerulosclerosis. The enhanced expression of activated prorenin was observed in the kidneys of diabetic rats that were treated with vehicle, whereas it was markedly suppressed in the kidneys of diabetic rats that were treated with PRRB but not ACEi. These results suggest that (pro)renin receptor blockade does not only inhibit the progression of nephropathy but also reverses the glomerulosclerosis that has already developed in diabetic rats.

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