Myeloid-specific Exoc5 deficiency develops renal inflammation and hypertension

Migration of macrophages into the kidney is a cause of inflammation and the pathogenesis of hypertension. The exocyst complex drives polarized exocytosis and cell migration, although the roles of the exocyst complex in macrophage infiltration have yet to be fully understood. Here, we determined the pathophysiological role of Exoc5, a major component of the exocyst complex, in the development of hypertension using myeloid-specific Exoc5-deficient (LysM-Exoc5 KO) mice and cells. Selective elimination of Exoc5 expression in bone marrow-derived macrophages (BMDM) of LysM-Exoc5 KO mice elevated blood pressures (BP) compared to WT mice. Simultaneously, elevations in BMDM infiltration and expression of pro-inflammatory markers, such as F4/80, TNF-α, IL-6, and MCP-1, as well as angiotensin II and various sodium transporters, occurred in the kidneys of LysM-Exoc5 KO mice. LysM-Exoc5 KO BMDM demonstrated reduced release of exosomes containing formin1, accumulating formin1 inside the cell, and the enhanced BMDM migration was reversed by an actin disruptor and formin1 inhibitor. On the Other hand, levels of Rac1 and GTP-bound Rac1 were unchanged between LysM-Exoc5 KO and WT, nor did the Rac1 inhibitor show any effect on the migration. Silencing the Exoc5 gene in Raw264.7 cells reduced exosome release, leading to the accumulation of formin1 within cells, mimicking the LysM-Exoc5 KO phenotype. Exoc5-downregulated Raw264.7 cells injected into mice migrated into the kidney, inducing inflammation and increasing BP. These findings unravel an Exoc5-mediated selective exocytosis-regulated mechanism of inflammation and hypertension, providing Exoc5 and formin1 as potential therapeutic targets for hypertension.

Bone marrow-derived myeloid cells; Exoc5; Exocytosis; Formin1; Hypertension; Inflammation.