What is the clinical evidence from this study?

Study design: Other. Population: Aldosterone-induced cardiac and renal injury (n=36). Intervention: TAK-242 vs. Aldosterone-salt alone. Primary outcome: Systolic blood pressure (SBP) in mm Hg (p=<0.05).

November 10, 2015Open Access

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

Q: What are the key findings of this study?

TAK-242 significantly reduced systolic blood pressure and attenuated cardiac and renal hypertrophy, inflammation, and fibrosis in aldosterone-salt-treated rats.

Q: What does this research mean for the field?

The Toll-Like Receptor 4 (TLR4) antagonist TAK-242 significantly reduces systolic blood pressure and attenuates cardiac and renal hypertrophy, inflammation, and fibrosis in aldosterone-salt-treated rats. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Resultado clave

TAK-242 significantly reduced systolic blood pressure and attenuated cardiac and renal hypertrophy, inflammation, and fibrosis in aldosterone-salt-treated rats.

PICO estructurado

Does TAK-242 prevent aldosterone-induced cardiac and renal injury in a rat model?

Población

Adult male Wistar rats (weight, 240± 20 g), n=36

Intervención

Aldosterone-salt (1 mg/kg/day subcutaneous) plus TAK-242 (2 mg/kg/day) for 4 weeks

Comparador

Vehicle alone, Aldosterone-salt alone, or TAK-242 alone

Resultado

Hemodynamic, cardiac, and renal parameters (including blood pressure, hypertrophy, inflammation, and fibrosis markers) at 4 weekssurrogate

In a rat model of hyperaldosteronism, the TLR4 antagonist TAK-242 attenuated salt-sensitive hypertension and cardiorenal fibrosis, suggesting TLR4 as a potential therapeutic target.

Resultado numérico

Tasa de eventos absoluta: 139% vs 150%

valor p: p=<0.05

Limitaciones

The study did not find that TAK-242 significantly suppresses TLR4 expression, suggesting it inhibits the signaling pathway but not the receptor itself, which requires further investigation.

Resumen

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.

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