211 I nterventional and epidemiological studies have demon- strated an association between dietary sodium consumption and increases in blood pressure (BP). 1–3 However, ≈40% of individuals with hypertension do not demonstrate salt sensitiv- ity (SS) of BP, and even in those with SS of BP the underlying mechanism(s) remain largely unknown. To better understand the differential BP response to sodium loading, one promising approach is to study the interaction of dietary sodium intake with candidate genes involved in the regulation of salt and water homeostasis. A primary role of aldosterone and the mineralocorticoid recep- tor (MR) is to maintain sodium and water homeostasis. Activation of this process is initiated by translocation of an activated aldo- sterone/MR to the cell nucleus to modulate the expression of genes regulating electrolyte and fluid balance. 4 It has been docu- mented that aldosterone activation of MR can also lead to rapid phosphorylation and activation of proteins in the MAPK path- ways and increases in reactive oxygen species and intracellular calcium, among other effects. 5,6 Together these effects are com- monly referred to as aldosterone’s nongenomic actions. Several other steroid hormone receptors, eg, estrogen receptor-α, have been shown to have both genomic and nongenomic effects. 7,8 Striatin is a newly described protein that interacts with the estrogen receptor-α and MR and regulates their nonge- nomic actions. 9,10 Striatin is a highly conserved member of the WD-repeat family of proteins that possesses caveolin-1, calcium-calmodulin, and coil–coil conserved domains. 11,12 Our laboratory has reported that activation of MR by aldosterone increases striatin expression in kidney, heart and aortic tissue, and cultured endothelial cells. 13 Our group has also described that striatin is a novel mediator for aldosterone’s induction of phospho-extracellular signal–regulated kinases and rapid action of estrogen receptor-α to promote phosphorylation of endothelial nitric oxide synthase. 14 The objective of this study was to examine the in vivo rela- tionship between SS of BP and striatin. Toward this goal, we Abstract—Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor’s rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7–20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure. (Hypertension. 2015;65:211-217. DOI: 10.1161/HYPERTENSIONAHA.114.04233.) • Online Data Supplement Key Words: blood pressure ◼ polymorphism, single nucleotide ◼ striatin protein, mouse Received July 9, 2014; first decision July 21, 2014; revision accepted September 30, 2014. From the Division of Endocrinology, Diabetes and Hypertension, Department of Medicine (A.E.G., C.M.R., B.S., J.S.W., R.B., T.Y., B.M., W.M.H., J.R.R., G.K.A., L.H.P., G.H.W.) and Channing Department of Network Medicine (J.L.-S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica De Chile, Santiago, Chile (R.B.); Division of Internal Medicine & Nephrology and School of Internal Medicine, University of L’Aquila, San Salvatore Hospital, V.le San Salvatore, Coppito, Italy (C.F.); and Division of Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City (P.N.H.). *These authors contributed equally to this work. The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 114.04233/-/DC1. Correspondence to Gordon H. Williams, Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital/Harvard Medical School, 221 Longwood Ave, Boston, MA 02115. E-mail gwilliams@partners.org Variants in Striatin Gene Are Associated With Salt-Sensitive Blood Pressure in Mice and Humans Amanda E. Garza,* Chevon M. Rariy,* Bei Sun, Jonathan S. Williams, Jessica Lasky-Su, Rene Baudrand, Tham Yao, Burhanuddin Moize, Wan M. Hafiz, Jose R. Romero, Gail K. Adler, Claudio Ferri, Paul N. Hopkins, Luminita H. Pojoga, Gordon H. Williams © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.04233 Salt Sensitivity by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on March 25, 2016 http://hyper.ahajournals.org/ Downloaded from