Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide

Turner, Stephen T.; Boerwinkle, Eric; O’Connell, Jeffrey R.; Bailey, Kent R.; Gong, Yan; Chapman, Arlene B.; McDonough, Caitrin W.; Beitelshees, Amber L.; Schwartz, Gary L.; Gums, John G.; Padmanabhan, Sandosh; Hiltunen, Timo P.; Citterio, Lorena; Donner, Kati; Hedner, Thomas; Lanzani, Chiara; Melander, Olle; Saarela, Janna; Ripatti, Samuli; Wahlstrand, Bjoern; Manunta, Paolo; Kontula, Kimmo; Dominiczak, Anna F.; Cooper‐DeHoff, Rhonda M.; Johnson, Julie A.

doi:10.1161/hypertensionaha.111.00436

Cited by 104 publications

(118 citation statements)

References 23 publications

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“…A recent genome-wide association study (44) found that polymorphic changes in only a very limited number of genes were associated with increases in blood pressure. The strongest linkage involved polymorphisms in the gene for PKC␣.…”

Section: Discussionmentioning

confidence: 99%

ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase Cα knockout mice

Bao

Thai

Yue

et al. 2014

American Journal of Physiology-Renal Physiology

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The epithelial Na channel (ENaC) is negatively regulated by protein kinase C (PKC) as shown using PKC activators in a cell culture model. To determine whether PKC␣ influences ENaC activity in vivo, we examined the regulation of ENaC in renal tubules from PKC␣ Ϫ/Ϫ mice. Cortical collecting ducts were dissected and split open, and the exposed principal cells were subjected to cell-attached patch clamp. In the absence of PKC␣, the open probability (P o) of ENaC was increased three-fold vs. wild-type SV129 mice (0.52 Ϯ 0.04 vs. 0.17 Ϯ 0.02). The number of channels per patch was also increased. Using confocal microscopy, we observed an increase in membrane localization of ␣-, ␤-, and ␥-subunits of ENaC in principal cells in the cortical collecting ducts of PKC␣ Ϫ/Ϫ mice compared with wild-type mice. To confirm this increase, one kidney from each animal was perfused with biotin, and membrane protein was pulled down with streptavidin. The nonbiotinylated kidney was used to assess total protein. While total ENaC protein did not change in PKC␣ Ϫ/Ϫ mice, membrane localization of all the ENaC subunits was increased. The increase in membrane ENaC could be explained by the observation that ERK1/2 phosphorylation was decreased in the knockout mice. These results imply a reduction in ENaC membrane accumulation and P o by PKC␣ in vivo. The PKC-mediated increase in ENaC activity was associated with an increase in blood pressure in knockout mice fed a high-salt diet.protein kinase C␣; ENaC; renal tubules; single channels; knockout mice; hypertension EPITHELIAL NA CHANNELS (ENaC) are sodium-permeable ion channels located in the apical membrane of polarized epithelial cells primarily in the distal nephron, lung, and distal colon. In the distal nephron, ENaC activity is the rate-limiting step for Na ϩ reabsorption (16, 34); therefore, ENaC activity is critical for the physiological maintenance of systemic Na ϩ homeostasis and long-term control of blood pressure. Because of its central role in responding to changes in Na ϩ uptake, ENaC activity is tightly regulated; dysregulation of this channel has been linked to abnormal blood pressure in several genetic disorders including Liddle's syndrome (18, 37) and pseudohypoaldosteronism type 1 (9, 33, 41).ENaC can be regulated either by altering the amount of time the channel spends open (open probability or P o ) or by altering the density of functional channels (N) in the apical membrane of distal nephron epithelial cells. One signaling molecule that appears to alter ENaC activity is protein kinase C (PKC). Activation of PKC with phorbol esters reduces ENaC activity in the apical membrane of A6 cells, an amphibian renal cell line, and in rat principal cells (15). In contrast to the inhibitory effect on ENaC due to activating PKC, pharmacologically inhibiting PKC increases ENaC P o (23, 49). A6 cells, on which many of the experiments described above were performed, contain several different PKC isoforms; so that it is difficult to determine which isoform is responsible for the changes in E...

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Section: Discussionmentioning

confidence: 99%

ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase Cα knockout mice

Bao

Thai

Yue

et al. 2014

American Journal of Physiology-Renal Physiology

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“…A combined association study of the PEAR, GERAS, and NORDIL trials highlighted a significant variant of PRKCA, protein kinase C alpha, as significantly associated with DBP reduction in response to thiazides 91 . The SNP, rs16960228, was replicated in the GENRES study cohort.…”

Section: Plausible Variants Uncovered In Unbiased Analysesmentioning

confidence: 99%

A Physiologic Approach to the Pharmacogenomics of Hypertension

Eadon

Chapman

2016

Advances in Chronic Kidney Disease

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“…Significant individual differences in the therapeutic response to thiazides are observed, however (9). Moreover, genetic loss of NCC function in humans (6,10) and mice (3,11,12) causes a relatively mild salt-wasting phenotype, especially considering the significant contribution the thiazide-sensitive NCC makes to overall renal NaCl absorption.…”

Section: Introductionmentioning

confidence: 99%

Integrated compensatory network is activated in the absence of NCC phosphorylation

Grimm¹,

Lazo‐Fernandez²,

Delpire³

et al. 2015

J. Clin. Invest.

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Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide

Cited by 104 publications

References 23 publications

ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase Cα knockout mice

ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase Cα knockout mice

A Physiologic Approach to the Pharmacogenomics of Hypertension

Integrated compensatory network is activated in the absence of NCC phosphorylation

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