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

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

23Na magnetic resonance imaging of tissue sodium in healthy and hypertensive humans

Koop et al. Hypertension 2013, 61:635-640

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

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)

Mechanism of T cell activation by isoketal formation

Dendritic cell

T cell

Increased salt

ROS

Isoketals

ModifiedProteins

CD86 CD28

High salt increases CD86 expression in dendritic cells

Dend

ritic

Cel

ls *

NS Man HS

NS Man HSCD86

% o

f CD8

6+ce

lls

DCs

High salt/control media

Co-culture with CFSE loaded T cellsTo determine T cell proliferation

High salt treated DCs drive T cell proliferation

High salt treated DCs drive T cell proliferationCD

4CD

8

NS Man HS

CFSE NS Man HS

**

**

DCs:

DCs:

Effect of elevated interstitial sodium on DC activation

Monocytes

Elevated interstitialNaCl

ROS/isoketal-activated DCs

Myeloid-derivedDCsT cell

proliferation

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?)

High salt increases all NOX2 subunits and this is SGK1-dependent

SGK inhibitorNEDD4-2 inhibitor

NS--

M--

HS--

HS+-

HS++

***

****

*

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

Effect of elevated interstitial sodium on DC activation

Monocytes

Elevated interstitialNaCl

ROS/isoketal-activated DCs

Myeloid-derivedDCsT cell

proliferation

SGK-1

NAPDHOxidase