Hippo Signaling Regulates High-NaCl-Induced Increase in RORγt+ Pro-Inflammatory Lymphocytes.

Area of Science:

• Immunology
• Cardiovascular Science
• Molecular Biology

Background:

• Arterial hypertension is a global health concern, with dietary salt (NaCl) as a significant risk factor.
• Hypertension involves renin-angiotensin-aldosterone system activation, vascular remodeling, and increased Th17 lymphocytes, leading to end-organ damage.
• The direct impact of NaCl and molecular pathways on Th17 cell differentiation in hypertension remains unclear.

Purpose of the Study:

• To investigate whether NaCl, altered osmolarity, or angiotensin II directly induce Th17 cell differentiation.
• To identify the molecular pathways involved in NaCl-induced Th17 cell differentiation.
• To explore the role of the Hippo signaling pathway in salt-sensitive hypertension.

Main Methods:

• Primary splenocytes were treated with NaCl, mannitol, or angiotensin II.
• RORγt+ lymphocyte frequency and cytokine expression (IL-17, IL-22) were measured.
• Angiotensin II receptor expression, Hippo pathway activity, and TAZ phosphorylation were assessed.
• Verteporfin was used to inhibit TAZ and evaluate its effect on NaCl-induced Th17 lymphocyte increase.

Main Results:

• NaCl and mannitol, but not angiotensin II, increased RORγt+ lymphocytes and IL-17/IL-22 expression.
• NaCl inactivated the Hippo pathway in lymphocytes, decreasing TAZ phosphorylation and enhancing its coregulator function.
• Verteporfin-mediated TAZ inhibition blocked the NaCl-induced increase in RORγt+ lymphocytes.
• NaCl and angiotensin II both induced angiotensin II receptor expression.

Conclusions:

• Dietary salt (NaCl) promotes the differentiation of pro-inflammatory lymphocytes via regulation of the Hippo signaling pathway.
• The Hippo signaling pathway is implicated in the pathophysiology of salt-sensitive hypertension.
• Targeting the Hippo signaling pathway with small molecules presents a potential therapeutic strategy for salt-sensitive hypertension.