Abstract 487: Nitrosonifedipine Prevents the Progression of Diabetic Nephropathy via Attenuating the Expression of Intrarenal Angiotensinogen and Oxidative Stress

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Activation of the intrarenal renin-angiotensin system (RAS) has been demonstrated in the animal models of hypertension, diabetes and kidney diseases. RAS activation is triggered by the reactive oxygen species (ROS)-mediated process which leads to angiotensinogen (AGT) increase. We have previously reported that renal AGT expression and urinary AGT (UAGT) level show the increase consistent with the diabetic condition. In the kidney of diabetic nephropathy (DN), the generation of ROS and AGT seems to increase remarkably when the vicious cycle of high glucose-ROS-AGT-Ang II-ROS is activated. Nitrosonifedipine (NO-NIF) is a novel candidate antioxidative agent, which is converted from nifedipine under the light exposure. Although the ability of NO-NIF to block calcium channels is quite weak, its radical scavenging ability is more potent than nifedipine. We have already reported that NO-NIF reduces cytotoxicity of tumor necrosis factor-α in cultured human glomerular endothelial cells through its anti-oxidative effects. In this study, we investigated the effects of NO-NIF on renal AGT in DN using KKAy diabetic mice. UAGT and urinary albumin (UA) were elevated in KKAy mice (16 weeks old) compared with C57BL/6 mice, which were decreased by NO-NIF treatment (30 mg/kg/day, i.p., 4 weeks) (UAGT; 92.5 ± 40.4 vs 344.1 ± 115.5 ng/24hr, p<0.05, UA; 609.6 ± 151.5 vs 1415.2 ± 312.5 μg/24hr, p<0.05). Urinary N-acetyl-beta-D-glucosaminidase, an indicator of renal tubular dysfunction was also increased in KKAy mice compared with C57BL/6 mice, which was suppressed by NO-NIF (0.19 ± 0.02 vs 0.23 ± 0.03 U/24hr, p<0.05). However, there was no difference in the serum AGT between C57BL/6 mice and KKAy mice regardless of NO-NIF. The immunohistochemical staining revealed that renal AGT was predominantly localized in proximal tubular cells in KKAy mice, and the expression was significantly suppressed by NO-NIF. NO-NIF also reduced the ROS elevation detected by DHE staining in the kidney of KKAy mice. In addition, NO-NIF suppressed cytotoxicity of hydrogen peroxide in human kidney proximal tubule epithelial cell line. These findings suggest that NO-NIF prevents the progression of DN via the attenuation of intrarenal AGT and oxidative stress.

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