Background: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension. Methods: In Japanese patients with newly diagnosed, untreated hypertension (n ‫؍‬ 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D 1 receptor (D 1 R)-inhibited renal sodium transport. We used the multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (>10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D 1 R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n ‫؍‬ 18). Results: A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predic-

A common molecular variant of angiotensinogen (AGT), the precursor of the potent vasoactive hormone angiotensin II, has been incriminated as a marker for a genetic predisposition to essential hypertension in Caucasians (Jeunemaitre, X., F. Soubrier, Y. V. Kotelevtsev, R. P. Lifton, C. S. Williams, A. Charru, S. C. Hunt, P. N. Hopkins, R. R. Williams, J. M. Lalouel, and P. Corvol. 1992. Cell. 71:169-180). We now show that the same variant, T235, is associated with essential hypertension in Japanese patients. The observation of this association in a distinct, ethnically homogeneous population further substantiates an involvement of angiotensinogen in the pathogenesis of essential hypertension and has physiological, epidemiological, and evolutionary implications. (J. Clin. Invest.

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Abstract-The effect of selectively decreasing renal angiotensin II type 1 (AT 1 ) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT 1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT 1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT 1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT 1 receptors. AT 1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT 1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels. Key Words: receptors, angiotensin II Ⅲ rats Ⅲ kidney Ⅲ hypertension, essential Ⅲ proteinuria G enetic manipulations that increase the activity of the renin-angiotensin system (RAS) systemically 1-5 or in specific organs (eg, brain and kidney) elevate blood pressure. 6,7 For example, overexpression of angiotensinogen and renin in renal proximal tubules 6 or in neurons and glia cells in brain 7 increased blood pressure without increasing circulating renin levels. Systemic deletion or silencing of genes that regulate the RAS also decreases blood pressure. Thus, disrupting or silencing angiotensinogen 4 and angiotensinconverting enzyme 1 genes 8,9 or the angiotensin II type 1A receptor (AT 1A R) gene 10,11 in mice or rats decreases blood pressure. Decreasing the expression of liver angiotensinogen also decreases blood pressure in mice. 12 More recently, Crowley et al reported that nephrectomized AT 1A Ϫ/Ϫ mice with 1 transplanted AT 1A ϩ/ϩ kidney had higher blood pressures than those observed in unmanipulated AT 1A Ϫ/Ϫ mice or AT 1A Ϫ/Ϫ mice with a transplanted AT 1A Ϫ/Ϫ kidney but lower than the blood pressures in unmanipulated AT 1A ϩ/ϩ or AT 1A ϩ/ϩ mice with a transplanted AT 1A ϩ/ϩ kidney. 13 These studies showed the importance of renal and extrarenal factors in the regulation of blood pressure. However, there are no reports of the renal functional and blood pressure consequences of silencing the AT 1 R selectively in the kidney of rats with spontaneous hypertension. To test the ...