Renal Mechanisms of Hypertension in RGS2 Knockout Mice
Elizabeth
1
Owens ,
Li
1
Jie ,
2
Eguchi ,
Satoru
Harpreet
1
and Patrick Osei-Owusu
1
Singh ,
Kendall J.
3
Blumer
1Department
of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA,
2Department of Physiology, Temple University School of Medicine, Philadelphia, PA,
3Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO
Introduction
Hypertension is a leading risk factor for
cardiovascular morbidity and mortality due to its
contribution to the development of atherosclerosis,
renal failure, congestive heart failure and stroke. In
the U.S. the incidence of hypertension is high (~40%
of adults) and is becoming a world wide epidemic as
developing countries adopt Western diets and
sedentary lifestyles. Elucidating the molecular
mechanisms that contribute to hypertension will
improve treatment of this devastating disease.
I.
Hypertension in the absence of RGS2 is
associated with impaired glomerular filtration
rate and increased renal vascular resistance.
IV.
Pressure-natriuresis response is shifted
to the right without a change in slope of
the curve in RGS2-/- mice, and there is no
change in fractional sodium excretion.
VII.
RGS2 -/- mice have increased luminal
translocation of epithelial sodium
channel protein (alpha-ENaC).
(MAP: mean arterial pressure; FENa: fractional sodium excretion)
(MAP: mean arterial pressure; RBF: renal blood flow;
RVR: renal vascular resistance)
(Stewart A, Huang J, Fisher RA. RGS Proteins in Heart: Brakes on the Vagus. Frontiers in Physiology. 2012;3:95. doi:10.3389/fphys.2012.00095.)
Regulator of G protein signaling 2 (RGS2) controls G
protein coupled receptor (GPCR) signaling by acting
as a GTPase-activating protein for heterotrimeric G
proteins. Certain Rgs2 gene mutations have been
linked to human hypertension. Renal RGS2
deficiency is sufficient to cause hypertension in
mice; however, the pathological mechanisms are
unknown. Here we determined how the loss of
RGS2 leads to renal dysfunction.
We examined renal hemodynamics and tubular
function by monitoring renal blood flow (RBF),
glomerular filtration rate (GFR), sodium channel
expression and localization, and pressure natriuresis
in wild type (WT, RGS2+/+) and RGS2 null (RGS2-/-)
mice. Pressure natriuresis was determined by
increasing renal perfusion pressure (RPP) stepwise
with increases in blood volume to the kidneys, or by
systemic blockade of nitric oxide synthase with LNG-Nitroarginine methyl ester (L-NAME).
-------------------------------------------------------------------We conclude that RGS2 deficiency impairs renal
function and autoregulation by increasing renal
vascular resistance and reducing renal blood flow.
These changes impair renal sodium handling by
favoring sodium retention. The findings provide a
new line of evidence for renal dysfunction as a
primary cause of hypertension.
II.
V.
(NHE-3: proximal tubule sodium transporter; ENaC: distal tubule sodium transporter)
Wild type mice have a significantly higher
change in sodium excretion under LNAME
administration than do RGS2-/- mice.
Conclusions
RGS2 deficiency causes impaired renal function due
partly to decreased renal blood flow and augmented
renal vascular resistance, resulting from enhanced
vasoconstriction. These changes impair renal sodium
handling by favoring sodium retention. Normal levels
of RGS2 facilitate normal renal function by
maintaining renal blood flow.
RGS2-/- renal microvessels show an 11-fold
increase in perivascular fibrosis relative to
wild type vessels.
Model
(MAP: mean arterial pressure; RBF: renal blood flow; RVR: renal vascular
resistance; GFR: glomerular filtration rate; UNa+V: sodium excretion rate; UK+V:
potassium excretion rate; NO: nitric oxide, a vascular smooth muscle relaxant;
LNAME: NO synthase blocker)
III.
RGS2 deficiency causes decreased
sensitivity and magnitude of change in
RBF and RVR after a step increase in RPP.
VI.
ENaC expression is increased in WT
cortical cytosol compared to RGS2-/-, but
is similar in WT and RGS2-/- membrane.
Acknowledgements
The authors would like to thank members of the OseiOwusu lab at Drexel University and the Blumer lab at
Washington University.
The authors would like to acknowledge NIH Grants
(HL075632 and GM4459) to Ken Blumer and
institutional support to Patrick Osei-Owusu for funding.
(RBF: renal blood flow; RVR: renal vascular resistance;
RPP: renal perfusion pressure; MAP: mean arterial pressure)
(detergent-free extract: cytosol proteins; detergent extract: membrane-bound proteins;
ENaC: distal tubule sodium transporter; NHE-3: proximal tubule sodium transporter)
DISCLOSURES: NONE