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

Departments of Medicine and Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana

Submitted 27 December 2006 ; accepted in final form 27 March 2007

This study was performed to determine the effectiveness of the Rho kinase inhibitor and NF-B 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 NF-B 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, NF-B activity, renal ANG II contents (160 ± 25 vs. 84 ± 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor-1 (TGF-1) 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 NF-B activity, renal ANG II contents (103 ± 11 and 116 ± 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF-1 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-NF-B axis plays crucial roles in the development of ANG IIinduced renal injury independently from BP regulation.

hypertension

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