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Salt Activates Immune Cells to Promote Hypertension
Annet Kirabo, D.V.M., M.Sc., Ph.D.Research Instructor of Medicine
Laboratory of Dr. David Harrison
Division of Clinical Pharmacology
No Conflict of Interest to Disclose
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Mechanism of T cell activation by isoketal formation
Dendritic cell
T cell
Hypertensive stimuli
ROS
Isoketals
ModifiedProteins
Kirabo et al. Journal of Clinical Investigation, 2014, 124:4642-56
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23Na magnetic resonance imaging of tissue sodium in healthy and hypertensive humans
Koop et al. Hypertension 2013, 61:635-640
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p<0.05 p<0.001
Normal Salt
NS + gp91ds-tat
High Salt
HS + gp91ds-tat
Salt (mM)gp91dstat
150-
150+
190-
190+
High salt induces superoxide production in DCs and this is NADPH oxidase dependent
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High salt increases isoketal adducts in dendritic cells
% o
f Iso
keta
l+ce
lls
Dend
ritic
Cel
ls *
NS Man HS
NS Man HSD11 (Isoketals)
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Mechanism of T cell activation by isoketal formation
Dendritic cell
T cell
Increased salt
ROS
Isoketals
ModifiedProteins
CD86 CD28
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High salt increases CD86 expression in dendritic cells
Dend
ritic
Cel
ls *
NS Man HS
NS Man HSCD86
% o
f CD8
6+ce
lls
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DCs
High salt/control media
Co-culture with CFSE loaded T cellsTo determine T cell proliferation
High salt treated DCs drive T cell proliferation
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High salt treated DCs drive T cell proliferationCD
4CD
8
NS Man HS
CFSE NS Man HS
**
**
DCs:
DCs:
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Effect of elevated interstitial sodium on DC activation
Monocytes
Elevated interstitialNaCl
ROS/isoketal-activated DCs
Myeloid-derivedDCsT cell
proliferation
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Potential Role of SGK1 in DC NADPH oxidase activation
Known Actions
Stabilization of eNACin collecting duct
(via NEDD4-2 phosphorylation)
Activation of IL-17A production by T cells
Hypothesized Action
Modulation of NADPH oxidase expression
(via NEDD4-2?)
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High salt increases all NOX2 subunits and this is SGK1-dependent
SGK inhibitorNEDD4-2 inhibitor
NS--
M--
HS--
HS+-
HS++
***
****
*
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SGK1 mediates high salt-induced production of isoketals in dendritic cells
% o
f D11
+ce
lls
D11 (Isoketals) SGK1 Inhibitor: - - +NS HSHS
NS HS + SGK1 InhibitorHS
* *
Dend
ritic
Cel
ls
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Effect of elevated interstitial sodium on DC activation
Monocytes
Elevated interstitialNaCl
ROS/isoketal-activated DCs
Myeloid-derivedDCsT cell
proliferation
SGK-1
NAPDHOxidase