Inhibition of HDAC6 mitigates high-fat diet-induced kidney inflammation and hypertension via reduced infiltration of macrophages

• Published in: Biochemical and biophysical research communications 2024-11, Vol.735, p.150800, Article 150800
• Main Authors: Luong, Phuong Quynh, Lee, Gwan Beom, Kim, Jee In
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; blood pressure; brain; cell movement; Diet, High-Fat - adverse effects; genes; HDAC6; high fat diet; histone deacetylase; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; hypertension; Hypertension - drug therapy; Hypertension - pathology; immunohistochemistry; Inflammation; Inflammation - pathology; interleukin-6; Kidney; Kidney - metabolism; Kidney - pathology; kidneys; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; males; Mice; Mice, Inbred C57BL; Nephritis - etiology; Nephritis - metabolism; Nephritis - pathology; Obese hypertension; pathogenesis; therapeutics; Tubacin
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150800

Obesity-mediated hypertension is a worldwide problem. Recent research has indicated that chronic inflammation is associated with the pathogenesis of obese hypertension. Activated immune cells infiltrate target organs, such as arteries, kidneys, and brain, causing end-organ damage and hypertension. Histone deacetylase 6 (HDAC6) regulates the inflammatory cell activity mediating the production of inflammatory cytokines and may play a role in the crosstalk between inflammation and hypertension. In this study, we investigated the roles of HDAC6 in high-fat diet (HFD)-induced kidney inflammation and hypertension. Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD for 15 weeks. HFD-induced hypertension with increased HDAC6 activities in the kidney and bone marrow-derived macrophages (BMDM). When HFD group reached the hypertensive phase, each group of mice was intraperitoneally injected with vehicle or selective HDAC6 inhibitor Tubacin (1 mg/kg/day) for 14 days. Tubacin treatment lowered blood pressure (BP) of HFD-fed mice to the normal level with successful inhibition of HDAC6 activity. Immunohistochemical staining of F4/80, which is known as a macrophage marker, revealed that HFD promoted macrophage infiltration into the kidney. Consequently, pro-inflammatory factors TNFα and IL-6 gene expressions in the kidney were increased by HFD. Tubacin canceled HFD-induced macrophage infiltration and inflammation in the kidney. HDAC6 gene silencing and Tubacin treatment in Raw 264.7 cells also blocked the chemoattractant-stimulated cell migration in vitro. The results reveal the novel role of HDAC6 in BMDM migration, kidney inflammation, and high BP induced by HFD providing HDAC6 inhibitors as a therapeutic option for obesity-mediated hypertension. •HDAC6 plays a critical role in HFD-induced hypertension in mice.•HFD activates HDAC6 in the bone marrow-derived macrophages and kidney.•HDAC6 activation increases macrophage migration and infiltration into the kidney.•HDAC6 inhibitor ameliorates hypertension by inhibiting kidney inflammation.