title: Crucial role of Rho-nuclear factor-kappaB axis in angiotensin II-induced renal injury.
abstract: This study was performed to determine the effectiveness of the Rho kinase inhibitor and NF-kappaB 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-kappaB 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-kappaB activity, renal ANG II contents (160 +/- 25 vs. 84 +/- 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor-beta1 (TGF-beta1) 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-kappaB activity, renal ANG II contents (103 +/- 11 and 116 +/- 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF-beta1 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-kappaB axis plays crucial roles in the development of ANG II-induced renal injury independently from BP regulation.
authors.affiliation: Dept. of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006977:Hypertension, Renal / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011507:Proteinuria; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012234:Rho Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D012717:Sesquiterpenes / Q000627:therapeutic use; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D014662:Vasoconstrictor Agents
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger; D012234:Rho Factor; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C002669:parthenolide; D003094:Collagen