on June 30, 2008
Published online before print June 30, 2008, doi: 10.1161/HYPERTENSIONAHA.108.113977
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Submitted on March 27, 2008
From the San Raffaele Scientific Institute (P.M., C.L., M.S., L.Z., S.D.C., C.T., E.B., G.B.), Division of Nephrology, Dialysis, and Hypertension, Università "Vita-Salute" San Raffaele, Chair of Nephrology, Milan, Italy; and the Department of Cardiovascular Sciences (G.L., P.S.B., C.B., N.J.S.), University of Leicester, Leicester, United Kingdom. * To whom correspondence should be addressed. E-mail: manunta.paolo{at}hsr.it
or njs{at}le.ac.uk.
Abstract—The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for
Revised on April 14, 2008
Physiological Interaction Between
Paolo Manunta*; 
-Adducin and WNK1-NEDD4L Pathways on Sodium-Related Blood Pressure Regulation
-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling (P=0.009) and acute BP response to a saline infusion (P=0.021), BP lowering after thiazide treatment (P=0.008), and nocturnal systolic BP (P=0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides.
Key words: hypertension • genetic • sodium transport • kidney • blood pressure • tubular • renal
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