Myeloid-specific Exoc5 deficiency develops renal inflammation and hypertension

Area of Science:

• Cell Biology
• Physiology
• Immunology

Background:

• Macrophage infiltration into the kidney contributes to inflammation and hypertension.
• The exocyst complex regulates cell migration and exocytosis, but its role in macrophage infiltration is unclear.

Purpose of the Study:

• To investigate the pathophysiological role of Exoc5, an exocyst component, in hypertension development.
• To elucidate the mechanism by which Exoc5 influences macrophage migration and kidney inflammation.

Main Methods:

• Utilized myeloid-specific Exoc5-deficient (LysM-Exoc5 KO) mice and bone marrow-derived macrophages (BMDM).
• Analyzed blood pressure, kidney macrophage infiltration, inflammatory markers, and exosome release.
• Investigated the role of formin1 and Rac1 in Exoc5-deficient macrophage migration using inhibitors and gene silencing in Raw264.7 cells.

Main Results:

• LysM-Exoc5 KO mice exhibited elevated blood pressure, increased kidney macrophage infiltration, and heightened inflammatory markers.
• Exoc5-deficient BMDM showed reduced exosome release, intracellular formin1 accumulation, and enhanced migration, which was reversed by formin1 inhibition.
• Exoc5 downregulation in Raw264.7 cells mimicked the phenotype, and these cells induced inflammation and increased blood pressure when injected into mice.

Conclusions:

• Exoc5 plays a critical role in regulating macrophage exocytosis and migration, contributing to inflammation and hypertension.
• Exoc5-mediated selective exocytosis of formin1 is a key mechanism in hypertension pathogenesis.
• Exoc5 and formin1 represent potential therapeutic targets for hypertension.