Crucial role of Rho-nuclear factor- B axis in angiotensin II-induced renal injury

Ozawa Y, Kobori H. Crucial role of Rho-nuclear factorB axis in angiotensin II-induced renal injury. Am J Physiol Renal Physiol 293: F100–F109, 2007. First published April 4, 2007; doi:10.1152/ajprenal.00520.2006.—This study was performed to determine the effectiveness of the Rho kinase inhibitor and NFB inhibitor in renal injury of ANG II-infused hypertensive rats. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation (n 7) or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups (n 7 each) to receive one of the following treatments during the entire period: vehicle, Rho kinase inhibitor (fasudil; 3 mg kg 1 day 1 ip), or NFB inhibitor (parthenolide; 1 mg kg 1 day 1 ip). After 12 days of ANG II infusion, systolic blood pressure (BP; 208 7 vs. 136 3 mmHg), Rho kinase activity, NFB activity, renal ANG II contents (160 25 vs. 84 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor1 (TGF1) mRNA, interstitial collagen-positive area, urinary protein excretion (43 6 vs. 11 2 mg/day), and urinary albumin excretion were significantly enhanced compared with the Sham group. While fasudil or parthenolide did not alter systolic BP (222 and 190 21, respectively), both treatments completely blocked ANG II-induced enhancement of NFB activity, renal ANG II contents (103 11 and 116 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF1 mRNA, interstitial collagen-positive area, urinary protein excretion (28 6 and 23 3 mg/day, respectively), and urinary albumin excretion. Importantly, parthenolide did not alter ANG II-induced Rho kinase activation although fasudil abolished ANG II-induced Rho kinase activation. These data indicate that the Rho-NFB axis plays crucial roles in the development of ANG IIinduced renal injury independently from BP regulation.