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

by Selleckchem | Apr 10 2023

Aim: We aimed to identify new mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. Specifically, we hypothesized HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism.

Methods: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or high salt diet (4% NaCl) for two 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 that HS 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 dysfunction suggesting a humoral factor, we termed P lasma D erived E ndothelial-dysfunction M ediator (PDEM), mediates the endothelial dysfunction. 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.

Comments：

The aim of the study was to investigate the mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. The researchers hypothesized that HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism. To test this hypothesis, male Sprague Dawley rats were fed normal salt diet (NS) or HS for two weeks. The researchers assessed NO signaling by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. They also isolated kidney endothelial cells with magnetic activated cell sorting and measured HDAC1 activity.

The results of the study showed that HS impaired NO signaling in the afferent arteriole, which was restored by inhibition of HDAC1 with MS-275. HDAC1 activity was increased in kidney endothelial cells, supporting the hypothesis that HS impairs NO signaling through an HDAC1-dependent mechanism. The researchers found that the loss of NO was dependent on the diet of the blood donor rather than the diet of the kidney donor. They also identified a humoral factor, which they termed Plasma Derived Endothelial-dysfunction Mediator (PDEM), that mediates endothelial dysfunction. The plasma from HS-fed rats was sufficient to induce dysfunction, and antioxidants and the NOS cofactor restored NO signaling.

In conclusion, the study provides novel insights into the molecular mechanisms by which HS decreases renal microvascular endothelial NO signaling. It suggests that HS activates endothelial HDAC1 through PDEM, leading to decreased NO signaling. These findings may have implications for the development of new therapies for hypertension and kidney disease associated with high salt intake.