Endothelial Histone Deacetylase 1 Activity Impairs Kidney Microvascular NO Signaling in Rats fed a High Salt Diet

Area of Science:

• Renal physiology and cardiovascular research
• Endothelial cell biology
• Molecular mechanisms of diet-induced disease

Background:

• High salt (HS) intake is linked to endothelial dysfunction and reduced nitric oxide (NO) production in kidney microvasculature.
• The precise molecular pathways by which HS impairs NO signaling remain incompletely understood.

Approach:

• Investigated the role of histone deacetylase 1 (HDAC1) in HS-induced NO signaling impairment in rat kidney microvascular endothelial cells.
• Utilized a blood-perfused juxtamedullary nephron preparation and isolated kidney endothelial cells to assess NO signaling and HDAC1 activity.
• Identified a plasma-derived factor mediating endothelial dysfunction.

Key Points:

• HS diet impaired NO signaling in the afferent arteriole, which was reversed by HDAC1 inhibition.
• Increased HDAC1 activity was observed in kidney endothelial cells from HS-fed rats.
• A humoral factor, termed Plasma Derived Endothelial-dysfunction Mediator (PDEM), was identified as responsible for HS-induced endothelial dysfunction.

Conclusions:

• HS diet activates endothelial HDAC1 through PDEM, leading to decreased NO signaling in renal microvasculature.
• This study elucidates novel molecular mechanisms underlying HS-induced endothelial dysfunction.
• Findings suggest potential therapeutic strategies targeting HDAC1 or PDEM for managing salt-sensitive hypertension.