bENaC
Acts as a Mechanosensor in Renal Vascular Smooth Muscle Cells That Contributes
to Renal Myogenic Blood Flow Regulation, Protection From Renal
Injury and Hypertension
Heather
A. Drummond, David E. Stec
Heather A.
Drummond, David E. Stec, Department
of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal
Research, University of Mississippi Medical Center, Jackson, MS, 39216-4505,
USA
Correspondence to: Heather A.
Drummond, PhD, Associate
Professor, Department of Physiology and Biophysics, Center for Excellence in
Cardiovascular-Renal Research, University of Mississippi Medical Center,
Jackson, MS, 39216-4505, USA.
Email: hdrummond@umc.edu
Telephone: +1-601-984-1812 Fax:
+1-601-984-1833
Received: May 6, 2015
Revised: May 27, 2015
Accepted: May 31, 2015
Published online: June 26, 2015
ABSTRACT
Pressure-induced
constriction (also known as the myogenic response) is an important
mechanodependent response in small renal arteries and arterioles. The response
is initiated by vascular smooth muscle cell (VSMC) stretch due to an increase
in intraluminal pressure and leads to vasoconstriction. The myogenic response
has two important roles as a mechanism of local blood flow autoregulation and
protection against systemic blood pressure-induced microvascular damage.
However, the molecular mechanisms underlying initiation of myogenic response
are unresolved. Although several molecules have been considered initiators of
the response, our laboratory has focused on the role of degenerin proteins
because of their strong evolutionary link to mechanosensing in the nematode. Our
laboratory has addressed the hypothesis that certain degenerin proteins act as
mechanosensors in VSMCs. This article discusses the importance of a specific
degenerin protein, Epithelial Na+ Channel (ENaC), in pressure-induced
vasoconstriction, renal blood flow and susceptibility to renal injury. We
propose that loss of the renal myogenic constrictor response delays the
correction of renal blood flow that occurs with fluctuations in systemic
pressure, which allows pressure swings to be transmitted to the
microvasculature, thus increasing the susceptibility to renal injury and
hypertension. The role of ENaC in myogenic
regulation is independent of tubular ENaC and thus represents a non-tubular role for ENaC in renal-cardiovascular homeostasis.
© 2015 ACT. All
rights reserved.
Key words: Autoregulation; Epithelial sodium channel; Blood
pressure; Mechanotransduction; Myogenic response
Drummond HA, Stec
DE. ENaC Acts as a Mechanosensor in Renal Vascular Smooth Muscle Cells That
Contributes to Renal Myogenic Blood Flow Regulation, Protection From Renal
Injury and Hypertension. Journal of
Nephrology Research 2015; 1(1): 1-9 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1189
INTRODUCTION
Mechanotransduction in vascular tissues is a topic of physiologic and
pathophysiologic importance. Chronic and transient mechanical forces contribute
to development of atherosclerosis, angiogenesis, endothelial function,
ischemia-reperfusion injury, myogenic constriction and hypertension. However,
the molecular mechanisms underlying transduction of mechanical forces,
particularly the transduction of transient mechanical forces into rapid changes
in cellular function, remain unclear. Our laboratory has been investigating the
molecular mechanism(s) underlying initiation of the myogenic response in renal
vasculature.
What is the myogenic response and why is it
important?
The myogenic response. The myogenic response was initially described
over 100 years ago[1]. The response is initiated by intraluminal
pressure-induced vessel wall stretch, which stretches VSMCs circumferentially
arranged around the vessel[2,3]. In turn, VSMC stretch initiates a
depolarization event, which is thought to activate secondary signaling
pathways, which include but are not limited to, voltage gated Ca2+
channels. Ca2+ channel activation stimulates Ca2+ influx
and triggers vasoconstriction (Figure 1A)[2,3]. The molecular mechanism underlying the
initial depolarizing event remains unresolved.
Physiological
significance of myogenic constriction: regulation of renal blood flow and
protection from injury. The myogenic response is important because it
participates in two processes. First, it is a mechanism of renal blood flow
autoregulation, where blood flow is tightly controlled despite changes in
systemic perfusion pressure between 50 and 150 mmHg[4,5]. Myogenic
constriction is fast acting and adjusts vascular resistance to a change in
perfusion pressure within 5-10 sec. The other mechanism of renal blood flow
autoregulation, tubuloglomerular feedback (TGF), is slower and adjusts vascular
resistance within 6-25 sec[6-9]. The fast nature of the myogenic
response has led investigators to suggest another purpose of the myogenic
response is the prevention of high systemic pressure transmission to the
glomerular microvasculature, thus protecting microvasculature from
pressure-related injury associated with hypertension, diabetes, and end stage
renal disease[10,11]. While much is understood about signaling
mechanisms underlying VSMC contraction, our understanding of the signaling
mechanisms that transduce changes in intraluminal pressure into a cellular
signaling event, i.e. the events that initiate myogenic constriction, is
limited. We hypothesize that degenerin proteins may act as mechanosensors that
transduce stretch into a cellular event.
Evolutionary role of degenerin proteins as
mechanosensors
Degenerin proteins are a large family of proteins expressed in a diverse
range of species, including the nematode, Caenorhabditis elegans (C.
elegans), Drosophila and mammals. This family has strong evolutionary ties
to mechanotransduction in neuronal and muscle tissues[12-21].
Members of this family share a common structure: intracellular N- and C-
termini and a single large extracellular domain of approximately 400 residues
separated by two membrane-spanning domains. Many of the degenerin proteins form
homo- and heteromultimeric, non-voltage gated, Na+/cation channels[14,15,19].
In mammals,
two subfamilies of degenerin proteins have been identified: the Epithelial Na+
Channel (ENaC) and Acid Sensing Ion Channel (ASIC) proteins. ENaC proteins are known for
their role in Na+ and water transport in the kidney, lung, and colon
epithelia. In these tissues, and ENaC proteins form a non-voltage gated, Na+ selective ion channel. The ENaC channel is
inhibited by submicromolar to low micromolar concentrations of the diuretic
amiloride and its analog benzamil. ENaC proteins are also expressed at several
important sites of mechanotransduction including somatic touch receptors in
skin, osteoclasts, keratinocytes, arterial baroreceptor neurons, endothelial
cells and VSMCs[16,22-26]. Because of their close evolutionary
relationship to the C. elegans degenerins, expression in
mechanosensitive tissues, and ability to form ion channels, ENaC proteins have
been considered as likely components of mechanosensors in vertebrate tissue.
A model for a
mammalian mechanosensor. Although a model of a mammalian mechanosensor has not
been established, numerous genetic studies have led to the development of a
mechanotransducer model in C. elegans neuronal and muscle tissue[18].
The model consists of three essential components: (1) an ion-conducting pore;
(2) extracellular matrix and proteins that may link the pore to the matrix; and
(3) cytoskeleton and proteins that may tether the pore to the cytoskeleton.
Degenerin proteins form the ion channel pore. The extracellular matrix
participates in force transduction and helps stabilize the ion-conducting pore
at the cell surface. The cytoskeleton may also participate in transduction of
the applied force and stabilize the ion-conducting pore at the cell surface.
Based on the concept of evolutionary conservation of function, we hypothesize
the mammalian mechanosensor is similar to the nematode model (Figure 1B).
Activation of the mechanosensor leads to influx of Na+ and/or Ca2+
through a degenerin ion channel, which leads to an initial membrane
depolarization and subsequent activation of VGCC.
Degenerin proteins are expressed in VSMCs and
mediate renal myogenic constriction
To consider ENaC proteins as mechanosensors mediating pressure-induced
constriction in blood vessels, ENaC proteins must be expressed in VSMCs and
located at the site of mechanotransduction, near the cell surface and ENaC
inhibition should abolish renal myogenic constriction. Therefore, initial
studies focused on the expression/localization of ENaC proteins in VSMCs and
the sensitivity of myogenic constriction to ENaC inhibition[23,27,28].
As shown in Figure 2A, VSMCs enzymatically dissociated from renal arterial
segments express and ENaC, but not , at or near the
cell surface membrane[27]. The localization pattern is significant
because a strain sensing mechanosensor might be predicted to be located near
the cell surface. The lack of ENaC in VSMCs is also an important finding. It has been suggested that
the lack of ENaC would render
a ENaC channel
unable to conduct current in VSMCs, however, this is not entirely accurate as and ENaC can form an
amiloride-sensitive, Na+ conducting channel in the absence of ENaC[29],
albeit with reduced current. Additionally, the possibility of another subunit,
such as an ASIC protein or unidentified ENaC, interacting with and ENaC to form a
channel has not been ruled out.
Our laboratory
has taken multiple approaches to determine the importance of ENaC proteins in
renal myogenic constriction, which includes (1) pharmacological inhibition; (2)
transient gene silencing and (3) genetically modified mice[27,30,31].
One of our methods for assessment of myogenic constriction is shown in Figure
2B-E. Renal interlobar artery segments are dissected from surrounding tissue
and mounted on two pipettes (Figure 2A). Artery segments are exposed to a
step-wise (25 mmHg, 5 min) increase in perfusion pressure (Figure 2C, with Ca2+
containing and then Ca2+ free extracellular solution. Under Ca2+
containing conditions, artery segments constrict in response to the increase in
pressure. However, under Ca2+ free conditions, vessels will
passively dilate in response to the increase in pressure (Figure 2D). Myogenic
tone at each pressure step is calculated as the difference in diameter between
Ca2+ containing and Ca2+ free conditions divided by Ca2+
free diameter. A vessel segment with a myogenic response will exhibit an
increase in tone with an increase in pressure. The pressure-myogenic tone
relationship will be flat in a vessel with a weakened myogenic response (Figure
2E). If degenerin proteins are important in the transduction of myogenic
constriction, then the relationship between pressure and myogenic tone should
be altered following degenerin inhibition.
To determine
if members of the degenerin protein family contribute to the transduction of
the myogenic response, we initially used broad-spectrum degenerin inhibitors
amiloride and its analog benzamil[27]. ENaC inhibition with benzamil
abolishes myogenic constriction in renal interlobar arteries in a concentration
dependent manner (Figure 2F). Amiloride, data not shown, elicited a similar
inhibition of myogenic constriction. An important factor in the interpretation
of these experiments is the selectivity of the ENaC inhibitors. At
submicromolar and low micromolar doses, benzamil is a fairly selective
inhibitor of ENaC. Furthermore, recent studies by Guan et al. and Nagasawa et
al. suggest myogenic constriction in rat afferent arterioles is also sensitive
to ENaC inhibition[32,33]. However, another study by Wang et al
found benzamil did not inhibit myogenic constriction in renal arterioles[34].
While
pharmacological inhibition is a tool for screening for degenerin involvement,
the contribution of specific subunits cannot be determined. Thus, to determine
the importance of ENaC and ENaC in renal myogenic constriction, we used a second approach, siRNA
and dominant-negative constructs. siRNA and dominant-negative constructs
specifically silence or ENaC expression
(~50-75%) in VSMCs in isolated mouse renal interlobar artery segments (Figure
2G and H)[31]. ENaC silencing inhibited pressure-induced constrictor
responses by 40-80%, without altering the ability of the vessel to constrict to
phenylephrine, suggesting the loss of vasoconstriction is specific to pressure
rather than a generalized loss in the ability of the vessel to constrict.
In our third
approach, we evaluated renal afferent arteriole myogenic constriction in a
mouse model with reduced levels of ENaC. The model, which is described in the following section, is
characterized by a global reduction in ENaC levels, including renal VSMCs. We examined
myogenic constriction using the attached afferent arteriole-glomerulus
preparation in which a single afferent arteriole attached to a glomerulus is
dissected from the kidney and perfused at 60, then 120 mmHg[30]. The
afferent arterioles from the ENaC +/+ mice develop significant myogenic tone in response to the step
increase in pressure. However, myogenic tone is nearly abolished in renal
afferent arterioles from ENaC m/m mice, suggesting ENaC is a critical to transduction of pressure-induced constriction
(Figure 3A). Thus, three separate lines of evidence suggest certain ENaC
proteins play a pivotal role in the myogenic response.
Do degenerin proteins mediate mechanically gated
currents?
While the studies addressed in the previous section demonstrate the
importance of degenerin proteins to the myogenic response, they do not
distinguish between a role as a mechanosensor that initiates the response or an
amplifying mechanism. Early investigations into the mechanosensitivity of ENaC
in heterologous systems were equivocal[16,35-38]. However, subsequent
studies using endogenously expressing tissue are supportive of ENaCs
mechanosensitivity. The application of negative pressure to isolated channels
in cortical collecting duct cells can gate native ENaC channels, and shear
stress can gate ENaC in both isolated rabbit cortical collecting duct and
heterologously expressing oocytes suggest ENaC channels can be activated by
mechanical forces[39-47]. However, not all mechanical forces are
created equal and mechanosensors might be expected to exhibit modal specificity.
For example, hypo-osmotic swelling and shear stress are mechanical forces, but
they are not necessarily equivalent. Is it appropriate to expect osmotic
swelling to activate a shear stress sensor? Based on our understanding of modal
specificity in somatic touch receptors, probably not. Therefore, we should
expect a mechanosensor that detects strain to be activated by stretch.
Since the importance of strain/stretch in activating a mammalian
degenerin has not been addressed, our laboratory developed a novel in-vitro
electrophysiologic assay to assess mechanically gated currents in isolated
VSMCs using stretch[48]. Briefly, enzymatically dissociated renal
VSMCs are plated on an elasmoteric substrate coated with collagen. Cells are
patched in a whole-cell configuration and the underlying membrane is stretched,
which in turn, stretches the VSMCs along its long axis (~2 µm). The stretch
initiates a small but rapid,
transient, Na+ dependent, inward current (Figure 3B). As expected,
the magnitude of the current is dependent on the magnitude of the stretch. The
current is nearly abolished in renal VSMCs obtained from ENaC m/m mice
(Figure 3C). These later data are very important as they demonstrate that
stretch gated currents in renal VSMCs are mediated by ENaC.
The ENaC m/m
mouse: a model to determine the physiological importance of ENaC mediated myogenic constriction
Our early studies using pharmacological and gene silencing approaches
indicated an important role for ENaC in myogenic constriction; however, understanding the consequences
of long-term loss of myogenic constriction on cardiovascular health required a
genetic model. For these studies, we used a model of reduced ENaC (ENaC m/m), rather
than ENaC knockout
mice as they die shortly after birth. The ENaC m/m model, developed by
Bernard Rossier and Edith Hummler at the University of Lausanne, Switzerland[49,50],
was generated using standard gene targeting approaches in the course of
generating a model of Liddles syndrome (increased ENaC) by the
insertion a premature stop codon in the C-terminus coding region. However, the
neomycin selection marker disrupts the ENaC gene locus resulting in
reduced ENaC expression.
Thus, a mouse model that under-, rather than over-expresses, ENaC was
generated. Mice homozygous for the mutation (m/m) express very low levels of ENaC
transcripts and/or protein in the lung, kidney and VSMCs, including renal
afferent arterioles[30,38,50-52]. Importantly, myogenic constriction
in the renal afferent arteriole is abolished, as addressed in the previous
section[30]. Since the afferent arteriole is the primary site of
development of vascular resistance in the kidney, ENaC mediated myogenic constriction
likely contributes to control of whole kidney vascular resistance and blood
flow regulation.
Myogenic
regulation of renal blood flow is attenuated in ENaC m/m mice
To address the physiologic and pathophysiologic
importance of ENaC mediated renal myogenic constriction in the regulation of whole
kidney blood flow (RBF), we used the ENaC m/m
mouse model. We utilized the temporal separation between the onset of the
myogenic mechanism (0-5 sec) and the TGF mechanism (6-25 sec) to determine the
contribution of ENaC to myogenic regulation of RBF[30,52].
In these studies, mice were instrumented with a carotid arterial catheter for
blood pressure measurement and a renal flow probe for measurement of whole
kidney blood flow (Figure 4A). A step increase in blood pressure was achieved
with an occlusion of the lower abdominal aorta, just below the renal artery
(Figure 4A, B). RBF increases and RVR decreases immediately following the step
increase in pressure (Figure 4C and D). Within 5-10 sec, RBF begins to return
to control levels in +/+ animals due to myogenically mediated increase in RVR.
In contrast, RBF remains elevated and RVR reduced in the m/m mice, suggesting a
loss of myogenic regulation.
We quantified
the speed of the myogenic mechanism by the determining the rate of change in
whole kidney RVR during the first 5 seconds following a step increase in renal
perfusion pressure (Slope RVR0-5sec, Figure 4E). In both studies, we
found a significant delay in the correction of RBF following a step increase in
perfusion pressure in ENaC m/m mice[30,52]. To minimize any confounding influence
of TGF, we examined renal hemodynamic responses to a step increase in pressure
following acute volume expansion to reduce the contribution of TGF to vascular
resistance[53-55]. We found myogenic speed was suppressed nearly 80%
(Figure 4E), findings that parallel our in-vitro findings (loss of myogenic
constriction in afferent arterioles) in ENaC m/m mice.
Signs of renal
inflammation and mild injury in the ENaC m/m mouse
Inappropriate regulation of RBF is linked to renal injury in
hypertension and diabetes[56,57]. Normally, swings in systemic
pressure are prevented from reaching delicate renal microvasculature because of
autoregulatory mechanisms; when systemic pressure rises, autoregulatory
mechanisms are activated leading to vasoconstriction, thus preventing
transmission of higher systemic pressures to delicate microvessels[56-59].
Since the myogenic response responds rapidly to changes in perfusion pressure,
it is considered an important mechanism to prevent transmission of pressure
swings to the microvasculature. We considered the possibility that ENaC m/m mice
might have signs of renal injury and possibly, elevated blood pressure due to
their reduced myogenic capacity. To address this possibility, we examined
kidneys for indicators of renal injury and found signs of inflammation and mild
renal injury characterized by increased levels of renal inflammatory cytokines
(TNF, IL1, IL6),
inflammatory cells (macrophages, lymphocytes), growth factors linked to
pressure-dependent injury (TGF), and mild expansion of extracellular matrix[51]. We also
found mean blood pressure is ~15 mm Hg higher than wildtype littermates (Figure
5)[51]. These findings demonstrate a link between altered ENaC mediated
myogenic function, renal injury and hypertension.
Why isnt the ENaC m/m mouse hypotensive?
Because the ENaC m/m mouse was generated using homologous
recombination, reduced levels of ENaC would be expected in all tissues,
including renal tubular cells. Loss of tubular ENaC related salt and water
transport would be expected to lead to reduced or normal blood pressure with
compensatory up-regulation of sodium retaining hormones. Thus, at first
consideration, our finding that blood pressure is elevated in the ENaC m/m may
seem counter-intuitive. However, when the elevated blood pressure data is taken
in context with loss of myogenic autoregulation and presence of renal
inflammation in the ENaC m/m, renal injury dependent increase in blood
pressure seems plausible (Figure 6).
Future
directions
There is much that needs to be done to elucidate the
role of degenerins in vascular function. Pressure-dependent renal injury is a
leading cause of end-stage renal disease with substantial financial costs
(Medicare Care costs exceeded $26 billion in 2010)[60,61].
Understanding the degenerin mediated protection from injury will lead to
development of approaches to prevent renal injury. Although the loss of renal
pressure-dependent vascular function in ENaC m/m mice does not lead to severe
renal injury and hypertension, it is not clear if a second hit, such as high
Na+ diet, elevated angiotensin II, or added psychological stress
would increase the severity of injury. Furthermore, information learned from
the renal circulation may also apply to other myogenically active circulations,
such as the cardiac and cerebral beds, which are often the targets of
hypertension-induced injury.
Another
important future direction is the determination of the identity of other
proteins that form the heteromultimeric mechanosensor in VSMCs. Based on the C.
elegans model, the mechanosensor is a large heteromeric complex in which
the pore is tethered to the cytoskeleton and extracellular matrix. The identity
of the other pore forming subunit(s) and the cytoskeleton and extracellular
matrix proteins responsible for tethering the pore have not been identified in
mammals. Understanding their identity and regulation by hormonal, inflammatory,
and autocrine factors may provide additional insight into the prevention and
treatment of renal injury. It is very likely that VSMC ENaC protein expression
and/or function may be altered in hypertension because many of the usual
suspects implicated in hypertension (i.e. endothelin, aldosterone, angiotensin
II, inflammatory cytokines, reactive oxygen species, and nitric oxide, dietary
salt) regulate epithelial ENaC expression[28,62-72].
Summary
Our laboratory has considered degenerin proteins, specifically ENaC,
as a component of a VSMC mechanosensor because of the strong evolutionary link
to mechanotransduction in C. elegans. This hypothesis is supported by
multiple lines of in-vitro and in-vivo evidence including (1) appropriate
protein localization; (2) disruption of myogenic constriction in isolated
vessels using pharmacological, transient gene silencing and genetically
modified animals; (3) disruption of stretch gated whole cells currents in renal
VSMCs and (4) disruption of myogenically mediated whole organ blood flow in
vivo (Table 1). Furthermore, the importance of degenerin mediated vascular
function on cardiovascular health is becoming clear; loss of vascular degenerin
function may inhibit the protective renal myogenic mechanism, thereby
increasing susceptibility to pressure related renal injury and hypertension.
Acknowledgements
This work was supported by NIH HL086996, P01HL051971, P20GM104357 as
well as from the American Heart Association- AHA 2041002.
CONFLICT OF INTERESTS
The authors declare no conflict of interest.
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Peer reviewer: Bianjiang
Liu, Department of Urology, The First Affiliated Hospital of Nanjing Medical
University, No. 300, Guangzhou Road, Nanjing 210029, China.
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