Endothelial histone deacetylase 1 activity impairs kidney microvascular NO signaling in rats fed a high‐salt diet
Year: 2024
Type: article
Abstract: AIM: We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism. METHODS: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. RESULTS: We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. CONCLUSION: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.
Source: Acta Physiologica
DOI: 10.1111/apha.14201
Institutions: University of Alabama at Birmingham, UAB Medicine, Mayo Clinic
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,900
Awards: Integrating novel mechanisms controlling sodium excretion and blood pressure, PRedoctoral Interdisciplinary training in renal physiology and MEdicine (PRIME), TLR4 in the Regulation of Renal Microvascular Function, HDAC1 Regulation of Endothelial NO, PURINERGIC REGULATION OF THE RENAL MICROVASCULATURE, Time Restricted Feeding in Diet Induced Obesity Improves Aortic Damage and Endothelial Function Through Reducing Th17 Cells, G5705031753, Novel mechanisms of salt-sensitivity and diurnal blood pressure rhythm, UAB Predoctoral Training Grant in Translational and Molecular Sciences, Novel Endothelial and Immunologic Mechanisms of Pathophysiology in Sickle Cell Disease, G9000301154, Timing of Diet and Kidney Pathophysiology in Diet-Induced Obesity, UAB Nutrition Obesity Research Center (NORC), PRedOctoral PhD and MD research training in TEams (PROmoTE)
OpenAlex ID: W4400654384