The natriuretic peptides (NPs) collectively represent a family of hormonal peptides that play important roles in the control of renal, cardiovascular, endocrine and skeletal homeostasis. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BMP)signal predominantly through the type A natriuretic peptide receptor (NPR-A), a single transmembrane domain receptor which links a ligand-binding extracellular domain to a particulate guanylyl cyclase domain at the carboxy terminus of the molecule. Studies carried out during the previous funding period have demonstrated that the transcription of the NPR-A gene (nprl) is controlled by a extracellular tonicity as well as the nuclear receptor ligand 1,25 dihydroxyvitamin D(VD). NPR-A expression in the inner medullary collecting duct is osmotically regulated and a significant portion of this regulation is signaled by the serum and glucocorticoid inducible kinase (sgk) which is itself induced by increased extracellular tonicity. We have identified a candidate element in the sgkl promoterwhich we believe controls its osmoregulation, and inferentially the osmoregulation of this transcriptional cascade. We will attempt to elucidate the molecular details that govern this osmoregulatoryactivity. VD has been shown to possess a variety of palliative effects in the cardiovascular system including reduction in blood pressure and suppression of cardiac hypertrophy. We hypothesize that some portion of the palliative effects of VD in the heart and vasculature may be mediated through upregulation of NPR-A levels and activity. In the present proposalwe will use a combination of in vitro studies in VDR -/- cells, in vivo studies involving murine models of genetic hypertension and knockout of the VDR selectively in vascular smooth muscle and renal collecting duct cells in an attempt to confirm the mechanistic link betweenVD's cardio- and vasculoprotective activity and stimulation of NPR-A expression/activity. Collectively, this proposal should provide us with a detailed understanding of how the NPR-A gene is regulated and the role that this regulation plays in the control of cardiovascular homeostasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Thrasher, Terry N
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Glenn, Denis J; Cardema, Michelle C; Gardner, David G (2016) Amplification of lipotoxic cardiomyopathy in the VDR gene knockout mouse. J Steroid Biochem Mol Biol 164:292-298
Sisley, Stephanie R; Arble, Deanna M; Chambers, Adam P et al. (2016) Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight. Diabetes 65:2732-41
Ni, Wei; Glenn, Denis J; Gardner, David G (2016) Tie-2Cre mediated deletion of the vitamin D receptor gene leads to improved skeletal muscle insulin sensitivity and glucose tolerance. J Steroid Biochem Mol Biol 164:281-286
Glenn, Denis J; Cardema, Michelle C; Ni, Wei et al. (2015) Cardiac steatosis potentiates angiotensin II effects in the heart. Am J Physiol Heart Circ Physiol 308:H339-50
Ni, Wei; Watts, Stephanie W; Ng, Michael et al. (2014) Elimination of vitamin D receptor in vascular endothelial cells alters vascular function. Hypertension 64:1290-8
Chen, Songcang; Gardner, David G (2013) Liganded vitamin D receptor displays anti-hypertrophic activity in the murine heart. J Steroid Biochem Mol Biol 136:150-5
Gardner, David G; Chen, Songcang; Glenn, Denis J (2013) Vitamin D and the heart. Am J Physiol Regul Integr Comp Physiol 305:R969-77
Glenn, Denis J; Wang, Feng; Nishimoto, Minobu et al. (2011) A murine model of isolated cardiac steatosis leads to cardiomyopathy. Hypertension 57:216-22
Chen, Songcang; Law, Christopher S; Grigsby, Christopher L et al. (2011) Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 124:1838-47
Chen, Songcang; Law, Christopher S; Gardner, David G (2010) Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity. J Steroid Biochem Mol Biol 118:135-41

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