Sodium homeostasis is critical for maintenance of normal blood pressure. The collecting duct (CD) is integral to the physiological regulation of natriuresis through control of CD Na+ transport processes. Our PPG group has delineated that the ET-1/ETB pathway in the CD is a major component of controlling blood pressure and Na+ homeostasis. Activation of the NOS/NO pathway in the CD is necessary for ET-1/ETB mediated inhibition of Na+ reabsorption by the epithelial Na+ channel (ENaC) and subsequent Na+ excretion. The mechanism of NOS activation, specifically the distinct activation of NOS1 and NOS3 isoforms, and the relationship with the ET-1/ETB pathway in the CD are obscure. We discovered a novel high salt-induced regulatory pathway mediated by histone deacetylase 1 (HDAC1). HDAC enzymes catalyze lysine deacetylation of histones in the nucleus epigenetically regulating gene transcription. We found that high salt significantly increases renal HDAC1 expression. Renal medullary infusion of an HDAC1 inhibitor in high salt fed rats significantly increased blood pressure and blunted urinary ET-1 excretion. In preliminary studies, we found that over-expression of HDAC1 in IMCD cells up-regulates ET-1 mRNA expression. Interestingly, HDAC1 is a member of the molecular feedback loop of circadian transcriptional control genes, thus in coordination with project 1 we will determine whether HDAC1 regulates ET-1 expression in a circadian manner. HDAC enzymes also regulate lysine deacetylation of non-histone, cellular proteins in the cytosolic compartment. HDAC1 inhibition in rats on high salt diet also significantly reduced urinary NOx excretion. The CD, especially IMCD, is exposed to 10-fold increases in flow with high salt intake compared to low salt intake. We find that flow-induced NO production is Ca2+- and HDAC1-dependent in IMCD cells. Flow induces NOS1- and NOS3-derived NO production in IMCD cells. We find that CD NOS1 is localized in the cytosolic compartment and directly interacts with HDAC1. HDAC inhibition increases lysine acetylation of NOS1 without altering NOS1 expression in IMCD cells. NOS3 is absent in the cytosolic compartment of IMCD, thus we propose that HDAC1 regulation of NOS3 activity is mediated indirectly. High salt induces Thr495NOS3 dephosphorylation mediating increased NOS3 activity. Our preliminary studies show that renal medullary HDAC1 inhibition prevents Thr495NOS3 dephosphorylation in high salt fed rats. Protein phosphatase 1 (PP1) is implicated in the dephosphorylation of Thr495NOS3, thus we will determine whether HDAC1 activates PP1. The overall hypothesis is that high salt increases Na+ excretion via activation of CD HDAC1 dependent up-regulation of CD ET-1/ETB signaling along with NOS1 and NOS3 activity.

Public Health Relevance

PROJECT 3 NARRATIVE High sodium consumption contributes to vast numbers of cardiovascular-related deaths. Dysfunctional sodium excretion results in salt-sensitive hypertension. Our innovative data shows that high salt diet induces the enzyme, histone deacetylase, in the renal collecting duct to maintain normal sodium excretion and blood pressure control. We also found that histone deacetylase regulates the pro-natriuretic activation of endothelin- 1 expression as well as the activation of nitric oxide synthase in the collecting duct. The main goals of this proposal are to elucidate the mechanisms critical for salt-dependent activation of histone deacetylase and the pro-natriuretic factors to provide in-depth understanding of the physiological contribution of these mechanisms on sodium excretion and maintenance of blood pressure control.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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OH, Youngsuk
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University of Alabama Birmingham
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Gao, Yang; Stuart, Deborah; Takahishi, Takamune et al. (2018) Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. J Am Heart Assoc 7:
De Miguel, Carmen; Sedaka, Randee; Kasztan, Malgorzata et al. (2018) Tauroursodeoxycholic acid (TUDCA) abolishes chronic high salt-induced renal injury and inflammation. Acta Physiol (Oxf) :e13227
Johnston, Jermaine G; Pollock, David M (2018) Circadian regulation of renal function. Free Radic Biol Med 119:93-107
Ramkumar, N; Stuart, D; Abraham, N et al. (2018) Nephron prorenin receptor deficiency alters renal medullary endothelin-1 and endothelin receptor expression. Physiol Res 67:S127-S136