TAK-242, a Toll-Like Receptor 4 Antagonist, Protects against Aldosterone-Induced Cardiac and Renal Injury

• Published in: PloS one Vol. 10; no. 11; p. e0142456
• Main Authors: Zhang, Yide, Peng, Weisheng, Ao, Xiang, Dai, Houyong, Yuan, Li, Huang, Xinzhong, Zhou, Qiaoling
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-11-2015; Public Library of Science (PLoS)
• Subjects: Acute Kidney Injury - blood; Acute Kidney Injury - chemically induced; Acute Kidney Injury - physiopathology; Acute Kidney Injury - prevention & control; Aldosterone; Animals; Cytokines; Cytokines - blood; Diabetes; Drug therapy; Endocrine disorders; Fibrosis; Heart; Heart diseases; Heart Diseases - blood; Heart Diseases - chemically induced; Heart Diseases - physiopathology; Heart Diseases - prevention & control; Hemodynamics - drug effects; Hemodynamics - physiology; Hypertension; Hypertrophy; IL-1β; Immunoglobulins; Inflammation; Inflammation - blood; Inflammation - chemically induced; Inflammation - physiopathology; Inflammation - prevention & control; Kidney diseases; Male; Mesenchyme; Monocyte chemoattractant protein 1; Nephrology; Pathogenesis; Physiological aspects; Protective Agents - pharmacology; Protective Agents - therapeutic use; Rats; Rats, Wistar; Renal function; Risk factors; Rodents; Salt; Salts; Signal transduction; Signaling; Studies; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TLR4; TLR4 protein; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-like receptors; Tumor necrosis factor-α; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142456

Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays an important role in the pathogenesis of hypertension and renal fibrosis. Toll-like receptor 4 (TLR4) signaling contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo-induced hypertension and renal damage is not clear. In the current study, rats were treated with Aldo-salt combined with TAK-242 (a TLR4 signaling antagonist) for 4 weeks. Hemodynamic, cardiac and renal parameters were assayed at the indicated time. We found that Aldo-salt-treated rats present cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of TLR4 as well as levels of molecular markers attesting inflammation and fibrosis are increased by Aldo infusion, whereas the treatment of TAK-242 reverses these alterations. TAK-242 suppresses cardiac and renal inflammatory cytokines levels (TNF-a, IL-1β and MCP-1). Furthermore, TAK-242 inhibits hypertension, cardiac and renal fibrosis, and also attenuates the Aldo-induced Epithelial-Mesenchymal Transition (EMT). In experimental hyperaldosteronism, upregulation of TLR4 is correlated with cardiac and renal fibrosis and dysfunction, and a TLR4 signaling antagonist, TAK-242, can reverse these alterations. TAK-242 may be a therapeutic option for salt-sensitive hypertension and renal fibrosis.