Beraprost sodium, prostacyclin analogue, attenuates glomerular hyperfiltration and glomerular macrophage infiltration by modulating ecNOS expression in diabetic rats.
Stable prostacyclin analogue, beraprost sodium (BPS) has recently been reported to attenuate glomerular hyperfiltration in diabetic rats, however, the mechanism has been still unknown. We previously reported that overexpression of endothelial cell nitric oxide synthase (ecNOS) in afferent arterioles and glomeruli induce inappropriate dilatation of afferent arterioles and glomerular hyperfiltration through overproduction of nitric oxide in early stage of diabetic nephropathy. In this study, we tested the hypothesis that BPS ameliorates glomerular hyperfiltration through modulating ecNOS expression in diabetic nephropathy. Furthermore, we examined the effects of BPS on the expression of intercellular adhesion molecule-1 (ICAM-1) and macrophage infiltration in diabetic glomeruli, because glomerular hyperfiltration induces the expression of ICAM-1 resulting in macrophage infiltration. Male Sprague-Dawley (SD) rats were administered continuously with BPS for 4 weeks after induction of diabetes by streptozotocin. In diabetic rats, the diameters of afferent arterioles, glomerular volume, creatinine clearance and urinary excretion of albumin and NO2/NO3 were increased as compared with non-diabetic control rats. Treatment with BPS improved these changes. The expression of ecNOS was increased in afferent arterioles and glomeruli in diabetic rats and suppressed by BPS. Prostacyclin receptor was expressed along afferent arterioles. Our results suggest that BPS attenuates glomerular hyperfiltration by modulating ecNOS expression in early stage of diabetic nephropathy. Moreover, BPS may inhibit ICAM-1-dependent infiltration of macrophages in diabetic glomeruli.
Yamashita
Tetsuji
T
Department of Medicine III, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
Shikata
Kenichi
K
Matsuda
Mitsuhiro
M
Okada
Shinichi
S
Ogawa
Daisuke
D
Sugimoto
Hikaru
H
Wada
Jun
J
Makino
Hirofumi
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; C048081:beraprost; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat