Caveolin-1 in renal disease

Abstract

p>Caveolin-1 is the essential structural formation for lipid raft formation. It has been ascribed to several disease processes in humans due to its ubiquitous distribution. Patients with chronic kidney disease suffer great morbidity and mortality where manipulation of caveolin-1 could lead to new potential therapeutic targets in this patient group. This review highlights caveolin-1 structure, signalling and provides examples of studies of caveolin-1 single nucleotide polymorphism in chronic kidney disease.</p

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Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-0014. DOI: http://dx.doi.org/10.17352/sjggt.000016
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http://dx.doi.org/10.17352/sjggt.000016DOI
Abstract
Caveolin-1 is the essential structural formation for lipid raft formation. It has been ascribed to several
disease processes in humans due to its ubiquitous distribution. Patients with chronic kidney disease suffer
great morbidity and mortality where manipulation of caveolin-1 could lead to new potential therapeutic
targets in this patient group. This review highlights caveolin-1 structure, signalling and provides examples
of studies of caveolin-1 single nucleotide polymorphism in chronic kidney disease.
Review Article
Caveolin-1 in renal disease
Sourabh Chand*
Renal Department, Shrewsbury and Telford NHS Trust,
UK
Received: 29 June, 2018
Accepted: 26 July, 2018
Published: 28 July, 2018
*Corresponding author: Sourabh Chand, Renal Depart-
ment, Shrewsbury and Telford NHS Trust, UK,
E-mail:
https://www.peertechz.com
Introduction
Chronic kidney disease (CKD) is a major global public health
issue that affects estimates of 10-16% of the general population
in developed countries leading to premature morbidity and
mortality [1]. In 2009-2010, the economic burden of chronic
kidney disease (CKD) on the English National Health Service
(NHS) was an estimated £1.45 billion (equivalent to 1.3% of
all NHS spending that year), with over half of the costs related
to the 2% of the CKD population with end-stage renal disease
(ESRD) requiring renal replacement therapy (RRT) [2]. The
resultant effect of the CKD burden is an excess in length of
stay in hospitals, hospital associated infections as well as an
excess of 7000 cerebral vascular events and 12000 myocardial
infarctions compared to age/gender matched controls [2].
Thus, it remains paramount to identify individuals with CKD at
the earliest time-point in order to instigate therapy to prevent
the progression to ESRD.
Caveolae are sub-class of non-clathrin coated lipid
rafts that were morphologically fi rst identifi ed in 1953 via
transmission electron microscopy and appear as little cave-like
invaginations of the plasma membrane of 50-100 nanometres
in size [3]. In 1955, Yamada fi rst described caveolae existing in
the renal mouse glomerular capillary endothelium [4]. Caveolae
are ubiquitously distributed though predominately found in
endothelial cells, epithelial cells, striated and smooth muscle
cells, fi broblasts and type 1 pneumocytes, with almost twenty
percent of the total plasma membrane of adipocytes being
occupied by caveolae [5,6]. There are three main isoforms of
the caveolin protein, with caveolin-1 (CAV1) being essential for
the formation of caveolae. In 1999, caveolin-2 was described as
20-kDa protein that co-localises and is dependent on CAV1 to
form hetero-dimers [7] and caveolae membrane localisation to
the basolateral surface of epithelial cells, whilst caveolae with
CAV1 alone, are not seen on the apical surface [8]. Caveolin-3
has a similar morphology to caveolin-1, and is mostly found in
cardiac, smooth and skeletal myocytes [9].
Caveolae are largely composed of cholesterol with
concentrated glycosphingolipids and sphingomyelin relative
to the plasma membrane distribution, with CAV1 required
for its structural stability. As shown in fi gure 1, caveolae can
form either the classical omega or little cave, enlongated (for
channel formation) or a direct vesicle formation mostly at the
basolateral surface [10]. This depends on the proteins called
cavins whose abundance changes the mobility of CAV1 and
thus structural integrity of the caveolar structure allowing the
structure and its contents to be endocytosed. If the ratio of
cavin-1 to cavin-2 is higher, then the caveolae omega shape
DŽĚŝĮĞd from RothbĞrg Ğt al (10) and ChidloǁĞƚĂů(11). Cav-1, cavĞŽůŝŶ-1; Cav-Ϯ͕ĐĂǀĞolin-2. Bar on
ĞůĞctron micrograph is 25 micromĞƚĞƌƐ
Figure 1: Electron micrograph and schematic representation of caveolae
structures.

008
Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-014. DOI: http://dx.doi.org/10.17352/sjggt.000016
is favoured; if cavin-2 expressed levels higher than cavin-1,
then the elongated shape is formed whilst cavin-3 expression
directs vesicle formation [11]. Depletion of cholesterol results in
decreased CAV1 expression that can also lead to destabilisation
of the caveolae structure to become mobile from the plasma
membrane.
Caveolin-1 is a protein that remains intracellular, formed
via the endoplasmic reticulum (ER) system and transported
from the Golgi apparatus to the plasma membrane. CAV1
exit from the Golgi apparatus is accelerated by increasing
cholesterol and inhibited after glycosphingolipid depletion
[12]. There are two isoforms of CAV1, alpha of 178 amino acid
length and beta which is 31 amino acid lengths shorter, with
the former isoform having a higher affi nity for the plasma
membrane. The N’ terminal and C’ termini face the cytoplasm,
after tyrosine phosphorylation and palmitoylation respectively.
Between the termini, there is a hairpin structure hydrophobic
domain of 32 amino acids (residues 102-134) that inserts to
plasma membrane and is involved in hetero-oligomerization of
CAV1 with caveolin-2 [13]. Residues 82-101 and 135-150 fl ank
this region, with the latter termed C’ membrane attachment
domain that contains a cis-Golgi targeting sequence. The N’
membrane attachment domain or caveolin scaffolding domain
(residue 82-101) is integral in membrane localisation and
anchoring of various proteins within caveolae and regulation
(both inhibition and enhancement) of their signalling activity
[5]. Another important site is the tyrosine-14 residue (Y14),
which requires phosphorylation for caveolar endocytosis and is
important in cell adhesion.
Caveolin-1 gene
The human caveolin-1 gene is located on the long arm
of chromosome 7, at genomic locus 7q31.1 (7:116540796) as
shown in fi gure 2. It consists of 3 exons (30, 165 and 342 base
pair in length respectively) and 2 introns (1.5 and 32 kilobases
in length) spaced in-between. The fi rst exons contain CpG
islands that via methylation are thought to be the main part
of CAV1 gene expression in cancer cell lines [14]. The third
exon harbours the functional oligomerisation, scaffolding,
transmembrane and C’ membrane attachment domains that
are highly conserved across species [15].
Caveolin-1 signalling
There are several roles of caveolae and CAV1 which are
integral to cellular function. The most common involves
vesicular transport of macromolecules (such as albumin) via
transcytosis from the luminal side of the capillary endothelium
to the interstitial space via membrane-bound vesicles. The
accumulation of gold-labelled albumin in the interstitial
space is not seen in the knockout CAV1 mouse by transmission
electron microscopy as compared to the wild-type mouse [16].
Endocytosis is the second example of vesicular membrane
traffi cking by caveolae. Caveolae share similar vesicle docking
and fusion molecules (soluble N-ethylmaleimide-sensitive
factor attachment protein receptors (SNARE) and dynamin)
as seen in the traditional clathrin-mediated endocytosis.
Pathogens such as Simian virus 40 and the cholera toxin utilise
collections of caveolae for internalisation into the cell, forming
with a distinct endosomal compartment with a neutral pH
called a caveosome, for delivery to the ER and Golgi apparatus
with recycling of CAV1 to the plasma membrane [5,17].
CAV1 and caveolae are also integral to cellular signalling
and signal transduction by compartmentalising receptors upon
ligand binding, acting as a chaperone of signalling molecules
and ligand bound receptors for delivery to the cell nucleus as
well as concentrating such events in the confi nes of a specifi c
subcellular environment [5]. Receptors such as the epidermal
growth factor receptor (EGFR) and transforming growth factor
beta (TGF) receptor are internalised by caveolae upon ligand
binding after phosphorylation of Y14 part of CAV1 [18]. This
internalisation is dependent on Src kinases and protein kinase
C [19]. Golgi derived CAV1 via SNARE protein syntaxin-6 is
also essential for plasma membrane delivery of receptors
angiotensin II type 1, insulin and the stretch activated channel
short transient receptor potential channel-1 [12].
In the majority, CAV1 effects are inhibitory upon cellular
signalling, acting to degrade receptors except in the case of the
insulin receptors. The main outcomes of CAV1 signal association
are pro-apoptotic and anti-fi brotic. The most commonly
described signalling CAV1 associations are with endothelial
nitric oxide synthase (eNOS) and TGF pathways. CAV1 via
its CSD binds eNOS resulting in its inactivity and can act as a
reservoir of inactivated eNOS. The infl ux of calcium leads to
more calmodulin recruitment and binding to the eNOS enzyme
leading to its release from bound CAV1 and thus restoration of
electron fl ow from NADPH to its reductase domain fl avins and
then to the heme moiety of eNOS, generating the vasodilator
nitric oxide (NO) from L-arginine. The generation of NO leads to
a dissociation of CAV1 scaffold, leading to termination of signal
transduction. However, if the substrate L-arginine becomes
limited, eNOS functions in an uncoupled mode, leading to the
electron transfer to the heme moiety to react with oxygen to
form reactive oxygen species (ROS) [20].
ROS releases TGF-1 from its latency-associated peptide
and latent TGF-binding protein to become activated [21]. Upon
this ligand binding, TGF type 1 receptor is phosphorylated
after binding with TGF type II receptor to form a serine/
threonine kinase heterotetrameric complex (Figure 3). If this
complex is internalised by the early-endosome antigen 1 non-
lipid/clathrin raft pathway, this phosphorylates the SARA/
Smad 2/3 complex downstream to induce a conformational
change that results in heteromerization of Smad 4 and
translocation to the nucleus to regulate transcription of pro-
fi brotic target genes as well as the downregulation of CAV1
The red rectangle shows the locaƟon of the caveolin-1 gene on chromosome 7
Figure 2: The caveolin-1 human gene on chromosome 7 and its three exons below
with size in base pairs (modifi ed from (5)).

009
Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-014. DOI: http://dx.doi.org/10.17352/sjggt.000016
and Smad 7 [22]. However, if the TGF receptor I/II complex is
internalised by caveolae, then SMURF/Smad 7 is recruited and
exerts a negative effect upon TGF signalling by proteasomal
degradation and ubiquitination of the TGF receptor complex
in CAV1 positive vesicles. In addition, CAV1 diminishes Smad
2 phosphorylation, disrupts its interaction with Smad 4, and
prevents Smad 2 translocation to the nucleus, further reducing
TGF signalling [22].
Other signalling events associated with caveolae endocytosis
involve fi bronectin degradation and integrin internalisation
[23,24]. The detachment of fi broblasts triggers ganglioside
GM1 internalisation via CAV1 and its Y14 phosphorylation; GM1
internalisation leads to Rac1 loss from the plasma membrane
and its reduced activation [12]. Thus not only is CAV1 important
in compartmentalising signal transduction in caveolae by
concentrating and localising signalling molecules by acting as
docking points for numerous cell surface receptors after ligand
binding, but also regulates cell adhesion, cell migration via 1-
integrins, extracellular matrix (ECM) interactions and acts as
fl ow sensors in endothelial cells and regulates stretch-induced
cell cycle progression [12,24]. CAV1 response to chronic shear
stress is to increase its levels with redistribution from the
Golgi complex to the plasma membrane and formation of
caveolae [25]. This leads to increased mechanosensitivity with
activation of signalling pathways such as eNOS and mitogen-
activated protein kinase (MAPK). With Cav1-/- mice, they
exhibit defects in chronic fl ow-dependent remodelling of blood
vessels [26]. Upon stretch, cell cycle progression is inhibited
with CAV1 downregulation or in Cav1-/- smooth muscle cells
through pathways including PI3 kinase-AKT/protein kinase B,
MAPK ERK, c-Src and integrins [27].
Caveolin-1 in renal adverse outcomes
Ca veolin-1 in renal fi brosis: As kidney function deteriorates
in CKD, more interstitial fi brosis is found amongst patients
irrespective of their underlying cause of CKD. CAV1 has been an
attractive protein to investigate in the context of organ fi brosis
as suggested with its effects described in the previous section
and the following section summarises renal fi brotic CAV1
research [28].
CAV1 interaction with TGF in fi brosis is a common
pathway by which renal and non-renal chronic disease
progresses and thus has been extensively investigated. Li et
al. used primary murine pulmonary endothelial cells that were
capable of obtaining a myofi broblast phenotype after TGF-1
stimulation, inducing SMA expression from wild-type cells.
Cav1-/- cells produced very high spontaneous levels of SMA
that was corrected upon CAV1 functional restoration using its
CSD peptide; thus CAV1 regulates endothelial-to-mesenchymal
transition in tissue fi brosis [29]. Ito et al. [30], showed that
adding hyaluronan with its receptor CD44 to immortalised renal
proximal tubular epithelial cells (HK2) led to an increase of
lipid raft internalisation of TGF via MAP kinase from the non-
lipid pathway predominance. The authors co-cultured HK2
cells with cells transfected with a Smad responsive promoter
and blocked several components (e.g. CD44 and its interaction
with hyaluronan) along this pathway to confi rm their fi nding.
As the authors state, this confl icts with previous work with
metastatic breast tumour cells that suggest hyaluronan
promoted the non-lipid pathway, and thus the fi nding may be
dependent on specifi c tissue microenvironments. Whilst Zhang
et al. [31], have shown stimulation with IL-6 led to more non-
lipid raft pathway dominance for the TGF receptor in HK2
cells and a decrease in the association of the IL-6 receptor
to CAV1 upon co-immunoprecipitation. This was after the
observation that IL-6 is only expressed on proximal tubular
epithelial cells at times of renal disease. However despite the
affi nity labelling fi ndings, it was noted that stimulation with
IL-6 and TGF-1 did not lead to an increase in Smad 2 or 3 or
7 protein expression, but only the luciferase assay suggested
more Smad activity.
As well as TGF, there have been many other signalling
events associated with CAV1 in renal fi brosis. Peng et al [32],
showed a Src dependent phosphorylation of the CAV1 Y14
site occurred with RhoA activation and formation of ROS
when they mechanically stretched mesangial cells via a cyclic
vacuum as a model of intraglomerular hypertension leading to
glomerulosclerosis. In the Cav1 knockout mouse, there was no
RhoA or ROS activation but this function was promptly restored
upon restoration of Cav1 [33].
As another model of hypertension, Bocanegra et al. [34],
investigated the protective profi le of losartan upon proximal
tubular cells from spontaneously hypertensive rats, whose
CAV1 expression was signifi cantly reduced compared to
control. Losartan (an angiotensin II type 1 receptor antagonist)
was noted to reduce ROS through Nox4 downregulation and
NADPH inactivation, through increased levels of CAV1 and co-
localisation with Heat shock protein 70. However two questions
remain: was this just a by-product of the blood pressure lowering
ability of losartan and why none of these effects were seen in
Figure 3: Schematic representation of TGFβ ligand (diamond yellow) receptor
complex I and II internalisation via clathrin and caveolae rafts (modifi ed from (28))

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Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-014. DOI: http://dx.doi.org/10.17352/sjggt.000016
the control group? The editorial comment focussed on the
mechanisms behind hypertension and ROS production causing
reduced renal function and structural damage; this was mainly
to inappropriate activation of intrarenal angiotensin II within
the proximal tubules due to its translocation of angiotensin
II type 1 receptor (AT1) from the plasma membrane to CAV1
rich domains. Here, CAV1 acts as a molecular chaperone to
AT1, providing a platform for redox signalling events through
NADPH oxidase dependent production of ROS via Nox4 [35].
Genetically obese Zucker rats on a casein diet have also
been shown to have reduced eNOS and raised CAV1 in renal
structural damaged kidneys as compared to those on a soy diet,
but again, CAV1 is known to fl uctuate with cholesterol levels
making it diffi cult to interpret the fi ndings [36]. From Valles et
al. [37], ureteric obstruction leads to an early rapid intrarenal
angiotensin II rise that leads to an increase in extracellular
matrix protein production and oxidative stress damage causing
fi brosis. Nitric oxide can ameliorate interstitial fi brosis and
in loss of eNOS leads to marked tubulointerstitial fi brosis
in the inducible NOS knockout mouse. CAV1 is expressed in
vascular endothelium, smooth muscle and epithelial cells
of the proximal, distal and convoluted tubules and ducts.
CAV1 also leads to apoptosis via inhibition of p42/44 MAP
kinase signalling. Thus the authors wished to look at the
role of CAV1 expression in congenital unilateral ureteropelvic
junction obstruction with grade IV hydronephrosis on imaging
requiring surgical intervention after vesico-ureteral refl ux
was excluded. The 19 children had ‘normal renal function for
their age’, were on no medication and were normotensive. The
scorers of interstitial volume and CAV1 staining were blinded.
There were two groups with group 1 split into subset A with
obstruction <1yr, subset B with obstruction >1yr, and group 2
had signifi cant renal impairment compared to group 1 (99mTc-
DPTA renal scan expression of kidney fi ltration rate 28.8±2%
to 39.7±2.1% respectively). The results showed group 2 CAV1
was present in the proximal tubule unlike control and group 1,
as well as co-localising with the AT1 receptor. Increased CAV1
expression was confi rmed on Western Blotting for protein
transcription from group 2’s urine. eNOS was low in group2
(p<0.01). Unfortunately the control was based on children with
renal cell carcinoma where it is known that CAV1 has expression
can be altered and may thus not act as a true control.
Further to the above human study suggesting increased
CAV1 expression in the more chronic and fi brotic group in
children, histological increased glomerular expression of CAV1
in Japanese patients has been identifi ed in diseases that target
the glomerulus such as diabetic nephropathy, membranous
nephropathy and focal segmental glomerulosclerosis [38].
It was also noted that CAV1 expression was also reduced
in glomerular endothelial cells with the use of steroids. In
diabetic nephropathy, murine Cav1 knockout led to a worse
glomerulosclerosis and albuminuria in the streptozotocin
model of type 1 diabetic nephropathy, though there is limited
tubulointerstitial fi brosis in this model [39]. CAV1 increased
expression was also noted in a streptozotocin rat model
of diabetic nephropathy with increased VEGF receptor 2
(VEGFR2)/CAV1 association in vivo [40]. In vitro, primary rat
mesangial cells after stimulation with VEGF, caused more CAV1/
VEGFR2, CAV1/Src expression and fi bronectin upregulation
via RhoA activation. Transfection of mesangial cells with an
overexpression of non-phosphorylatable CAV1 Y14 prevented
VEGF-induced RhoA activation and fi bronectin upregulation.
Another model of nodular glomerulosclerosis utilises human
urinary free light chains from patients suffering from light chain
deposition disease injecting to wild-type and Cav1 knockout
rats’ tail veins to induce nodular glomerulosclerosis. In the
Cav1 knockout, there was increased nodular glomerulosclerosis
and increased mesangial matrix production, however there was
a mix of gender used that may have infl uenced the results [41].
Other human studies have focussed on CAV1 in renal
transplantation. Yamamoto et al. [42], have previously
shown that de novo caveolae formation occurs in transplant
glomerulopathy in glomerular endothelial cells and now
investigate CAV1 in chronic active antibody mediated rejection
and thus transplant capillaropathy, where they found CAV1
to be associated with peritubular capillary endothelia that is
not normally present in healthy kidney. Pontrelli et al. [43],
also investigated chronic allograft nephropathy secondary
to immune system activation where CD40 is upregulated in
acute rejection in proximal tubular epithelial cells. This led to
increased Lyn phosphorylation and thus NFҡB activation. Lyn
phosphorylation is strictly associated with CAV1 and inhibiting
Lyn blocked the profi brotic induction of PAI-1.
Park et al. [44], have used an unilateral ureteric obstruction
(UUO) model in FVB/N mice to investigate the surge of stem
cells that occurs upon 10 days after ligation of the left ureter. In
the Cav1 knockout, the mesenchymal stem cell post obstructive
surge was blunted signifi cantly which led to no regeneration of
the parenchyma and marked fi brosis as measured by Sirius red
staining. Indeed some of the surge could be from the response
of the resident kidney stem cells. In this model, the FVB/N
wild-type mice are a different strain to the Cav1 knockout mice
and the control kidney was the contralateral kidney of each
mouse. These factors could affect the interpretation of their
fi ndings as different mouse strains have varying susceptibility
to fi brosis and the contralateral compensation after ligation of
the ureter could be different.
Chand et al. [45], also investigated the UUO model at day 3
and day 14 with sham operated mice being the same age, strain
and gender as mice undergoing UUO as their Cav1 knockout
mice. They showed that there was a more profound fi brosis
at day 14 of the UUO model with the Cav1 knockout mice than
their wild-type counterparts, but at day 3 the wild-type had
more fi brosis. The main difference was the abundance of F4/80
positive stained cells on confocal microscopy of frozen kidney
sections in the wild-type compared to the Cav1 knockout mice.
In summary, there appears to be negative effect of CAV1
expression leading to a worse renal phenotype especially in
glomerular disease. However, this is in opposition to the non-
renal literature where the CAV1 reduction in patient samples
or knockout of caveolin-1 in vitro has been found to lead to
a more fi brotic phenotype. This may be due to the organ and
microenvironment studied such as in bleomycin induced lung

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Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-014. DOI: http://dx.doi.org/10.17352/sjggt.000016
fi brosis [46], idiopathic pulmonary fi brosis [47], scleroderma/
systemic sclerosis [48], cardiac fi brosis [49], and keloid scars
[50], which involve more TGF dependent processes that are
reliant on the expression of CAV1 in fi broblasts.
Pleiotr opic effects of caveolin-1 in adverse renal out-
comes
As well as tubulointerstitial fi brosis, there are common
adverse outcomes experienced by patients with CKD as
their renal disease progresses. Due its ubiquitous nature of
distribution, CAV1 has been associated with many of these
outcomes.
Infection: In patients suffering from scleroderma associated
lung disease, their bronchoalveolar lavage revealed activated
monocytes and polymorphonuclear cells; these patients’
monocytes, neutrophils and T cells had a reduced expression
of CAV1 [50]. In mice exposed to lipopolysaccharide challenge,
the deletion of Cav1 led to a decreased expression of CD14
and CD36 during macrophage differentiation and suppressed
phagocytic ability and impaired bacterial clearance [51]. Cav1
knockout mice also had an increased mortality with induced
Pseudomonas aeruginosa and Klebsiella pneumoniae sepsis
[52,53]. In cystic fi brosis, effective internalisation of pathogens
such as Pseudomonas aeruginosa is required for an appropriate
immune response for its clearance; its internalisation is reliant
on CAV1 in type 1 pneumocytes and bladder epithelium [54].
CAV1 interaction with protein kinase C upon activation and
calcium release is essential for its translocation to caveolae
in order for production of infectious enveloped human
cytomegalovirus particles in fi broblasts [55]. Infection with
polyomavirus viraemia can cause BK nephropathy in renal
transplant recipients. Moriyama et al. in vitro data shows this
viral entry in human proximal tubular epithelial cells requires
co-localisation with CAV1 for caveolae entry into the cells [56].
Cardiovascular disease: CAV1 has been associated with
an infl ammatory macrophage phenotype that promotes
atherosclerosis by the production of foam cells [57]. Schwencke
et al. have found reduced CAV1 expression in VSMC of human
atheroma [58]. CAV1 also binds eNOS in an inactive state and
with an infl ux of calcium, its release thus affecting vascular
function [59]. In the Cav1 knockout mouse, cardiac hypertrophy
occurs despite the high presence of caveolin-3, in which the
latter is thought to be the predominant isoform of caveolin in
the heart [60].
Malignancy: CAV1 may have a tumour suppressive role
depending on the cancer type. CAV1 has been shown to promote
apoptosis and in Cav1 knockout mice, hyperactivation of the
p42/44 MAP kinase cascade and cyclin D1 upregulation in breast
cancer models lead to cancer progression and metastases [61].
CAV1 has been considered as a prognostic marker in several
cancers [62]. However, in prostate cancer, CAV1 upregulation
has been associated with progression of the malignancy [63],
highlighting CAV1 altered function depending on the organ
microenvironment studied.
Caveolin-1 single nucleotide polymorphism in renal
disease: Testa et al. found that there was a signifi cant
independent and interaction association between CAV1
rs4730751 and eNOS rs1799983 genotype and increased carotid
arterial intima thickness (vascular hypertrophy) and cross-
sectional area across the common carotid artery (arterial
remodelling) [64]. It is not clear if these associations occur in
non-dialysis CKD or just a phenomenon seen in haemodialysis
patients. eNOS is bound to CAV1 requiring a calcium infl ux for
its release from CAV1 in order to become activated.
Importantly, as CKD becomes more advanced the dominant
vascular lesion is arteriosclerosis and associated vascular
stiffness, rather than atheromatous disease as seen in the
general population [65]. Aortic pulse wave velocity (aPWV) is the
gold standard method for measuring arterial stiffness and has
been consistently associated with all-cause and cardiovascular
mortality in multiple conditions including CKD [66,67].
Independent of known clinical variables that infl uence aPWV in
multivariate analysis, Chand et al. found that CAV1 rs4730751 CC
genotype is associated with lower arterial stiffness in patients
with early and late stage non-dialysis CKD [68]. In vascular
endothelium CAV1 interacts with eNOS such that reduced CAV1
increases eNOS activity which may have a deleterious effect on
endothelial health and arterial stiffness, due to “uncoupling”
of eNOS which leads to the generation of superoxide anion
radicals [69], in oxidative stress characteristic of CKD [70].
Similarly, caveolin-1 defi cient aortic smooth muscle cells
have been shown to be pro-arteriosclerotic with increased
neointimal hyperplasia, cell proliferation and migration [71].
These observations may underlie the fi ndings of the current
study. Conversely, lower levels of CAV1 in macrophages are
associated with an anti-infl ammatory phenotype, reduced
foam cell formation and therefore protection from atheroma
[57]. Interestingly, these contrasting functions of CAV1 in
endothelium (“anti-arteriosclerotic”) and macrophages
(“pro-atheromatous”) may consolidate the fi ndings of the
current study whereby CC genotype associates with a reduced
aPWV (“anti-arteriosclerotic”) and the fi ndings of Testa et al.
[64], who showed an association between CC genotype and
increased carotid arterial intima media thickness (a measure of
atheroma rather than arteriosclerosis [72].
Anti-neutrophil cytoplasmic antibody (ANCA) associated
vasculitis represent a group of primary autoimmune disorders
that are systemic, mainly involving small to medium sized
vessels. Despite success in improving patient life expectancy,
there remains high mortality at 5 years (up to 28%) and
signifi cant morbidity associated with complications of the
disease and its treatment such as infection, cardiovascular
disease, malignancy and progression of kidney disease. These
complications mirror potential CAV1 effects, and indeed, the
CC genotype of CAV1 rs4739751 was associated with a better
outcome in this group of patients [73].
Donor CAV1 AA rs4739751 genotype of renal transplants are
associated with worsening renal allograft function, survival
as well as excess fi brosis upon histology in cohorts from
Birmingham [74], Belfast [74], and France [75].

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Citation: Chand S (2018) Caveolin-1 in renal disease. Scientific J Genet Gene Ther 4(1): 007-014. DOI: http://dx.doi.org/10.17352/sjggt.000016
Conclusion
CAV1 pleotropic effects and ubiquitous distribution makes
it an attractive therapeutic target in many human diseases
in particular with patients in CKD, either to reduce related
morbidity and mortality, as a biomarker for identifi cation of
high risk individuals, but also its direct manipulation in renal
fi brosis.
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Copyright: © 2018 Chand S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
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