R EVIEW
J NEPHROL 2006; 19: 21-29
Transient receptor potential channels
in the kidney: Calcium signaling, transport
and beyond
Paolo Menè
Department of Clinical Sciences, Second Medical School, University of Rome “La Sapienza”, Rome - Italy
Division of Nephrology, Sant’ Andrea University Hospital, Rome - Italy
ABSTRACT: Multiple cationic channels with variable selectivity for Ca2+, K+ and Na+ have been identified in smooth
muscle cells (SMC) as well as non-excitable cells. They control Ca2+ store refilling and depletion, G-protein-mediated
receptor activation, apoptosis and cell growth, membrane potential, intracellular pH, oxidative stress, phospholipid
signaling, and other critical cell functions. A novel superfamily of divalent cation channels has been recently characterized as highly conserved heterotetramer homologues of Drosophila transient receptor potential (TRP). At least 50
members of seven major TRP channel families have been identified to date. The involvement of TRP in store-operated Ca2+- gating has been demonstrated in various tissues, along with intestinal and renal epithelial cell Ca2+ and Mg2+
transport, indicating a role in total body homeostasis of divalent cations. TRPV5-null mice display phenotypic defects
including hypercalciuria and impaired bone mineral density. TRPP2 or polycystin 2 (PC2), encoded by the PKD2
gene, is an integral protein of epithelial cilia whose mutation is associated with autosomal dominant polycystic kidney
disease (ADPKD). A TRPP1 (polycystin 1)-PC2 channel complex is actually implicated in the transduction of environmental signals (i.e. luminal tubular fluid flow and composition) into cellular events, such as epithelial cell growth.
TRP channels can eventually play a role in the pathogenesis of arterial hypertension via direct effects on vascular
smooth muscle contraction, renal blood flow, glomerular hemodynamics and the tubular handling of Ca2+ and electrolytes.
Key words: Transient receptor potential, Store-operated Ca2+ channels, Receptor-operated Ca2+ channels, Epithelial Ca2+ transport,
Autosomal dominant polycystic kidney disease
INTRODUCTION
All living organisms exert thorough control on the intracellular microenvironment in spite of marked
changes in external ion composition and osmotic/
oncotic forces. Selective permeability of plasma membranes and the bidirectional transport of ions and
water is critical to the process. A number of cellular
activities depend on a host of channels, water and ion
transporters constitutively expressed on or translocated to the surface of cells in a regulated manner. Most
notably, the generation of a transmembrane potential,
which in excitable cells drives intercellular currents,
action potentials and contraction/relaxation cycles,
largely depends on the state of the opening of the ion
channels and the activity of transmembrane pump
proteins.
Many of these structures serve both as ion gates/carriers and signaling molecules, as certain ion fluxes encode for functional responses in target cells. This is
the case for a host of vasoconstrictors, such as angiotensins, endothelins and arginine vasopressin,
which induce internal Ca2+ redistribution or currents
in cells displaying the appropriate receptors (1, 2).
Transmembrane signals are also encoded by frequency or amplitude of oscillatory Ca2+ currents, in turn
actuated by cyclic membrane gating (3).
A superfamily of such channels, the so-called transient
receptor potential (TRP) channels, has recently
attracted considerable interest. TRP are heterotetrameric polypeptides initially identified as photoreceptors in insect retinal cells, and later recognized as
cation channels in a variety of sensing apparatuses
(including visual and hearing structures, such as
cochlea sensor y hair cells) (4-6). Cation influx
through these structures, particularly Ca2+, is typically
controlled by Ca2+ ions themselves, a process often referred to as “capacitative Ca2+ influx” or “Ca2+-activated Ca2+ influx” (7, 8). Selectivity of TRP channels for
divalent versus monovalent ions (eg, Ca2+ vs. Na+)
www.sin-italy.org/jnonline/vol19n1/
21
TRP channels and calcium in the kidney
ranges from >100:1 to 1:1, based on isoform structure
and tissue type. It is now recognized that TRP channels
are expressed in many different structures and organs,
and play a key role in Ca2+ transport in excitable cells,
including vascular contractile smooth muscle cells
(SMC), as well as in renal tubular cells and other
epithelia. In the kidney, one such channel is involved in
the regulation of the Ca2+ external balance, as recently
shown by the TRP-knockout mouse model, which exhibits hypercalciuria and skeletal defects consistent
with altered distal tubular reabsorption of Ca2+(9, 10).
The mutation of the components of the TRP superfamily of proteins are associated with long-known genetic diseases, such as adult polycystic kidney disease
(PKD), linked to polycystine 1 and/or 2 (PC2) defects
(11, 12). Inasmuch as renal ion transport is the key to
external balance and fluid homeostasis, and intracellular [Ca2+] ([Ca2+]i) is a major modulator of vascular reactivity, it is likely that TRP cation channels play a role
in the control of blood pressure (BP) and, therefore, also in the pathogenesis of arterial hypertension.
TRP, A SUPERFAMILY OF UBIQUITOUS DIVALENT
CATION CHANNELS
Mammalian homologues of Drosophila TRP proteins
form an ever growing list of ubiquitous Ca2+ and/or
Mg 2+-permeant, non-selective cation channels, of
which some 50 members have been identified to date
(4, 6, 13, 14). The TRP superfamily includes TRPA
channels, mostly involved in hearing, three homologous subfamilies (TRPC, TRPV and TRPM), and
three distantly related subfamilies (TRPP, TRPML and
TRPN or ANKTM1) (Tab. I). Importantly, TRP proteins assemble into heterotetramers to form native
channels, for example, variable combinations of distinct isoforms in ratios of 1:3, 1:2:1, etc. This implies
that the electrophysiology and the selectivity of a
channel are dictated by the heterogeneity of the assembled channels (13, 14). A typical classical - or
canonic (C) TRP protein, such as human TRPM3, is
composed of 1555 amino acids, encoded by a gene
comprising 24 exons mapping to chromosome
9q-21.12. Its structure includes six transmembrane
domains with cytoplasmic N- and C-termini, incorporating several putative regulator y sites, including
calmodulin/inositol (1, 4, 5)-trisphosphate (InsP3) receptor binding sites, PDZ binding motifs, phosphorylation sites for protein kinases, ankyrin-like repeats
and proline-rich motifs (4, 6, 13, 14) (Fig. 1). The
N- terminus displays a diacylglycerol (DAG) regulatory site. Many studies show direct TRPC regulation by
DAG, as in the case of TRPC3 expressed in Chinese
hamster ovary cells, or by related metabolites of phospholipase C, such as polyunsaturated fatty acids or
22
Fig. 1 - A schematic diagram of the structure of two prototypical TRP channels with six transmembrane-spanning
domains. TRPM2 (also labeled TRPC7 or LTRPC2) is a nonselective Ca2+ channel sensitive to H2O2, oxidative stress and
α. Note the C-terminal NUDT9 Nudix hydrolase domain,
TNF-α
which binds ADP-ribose or NAD with resulting conformational and ion gating changes. The TRP domain near the Cterminus is a highly conserved 25-amino acid stretch, sometimes replaced by a kinase or phosphatase domain (“chanzymes”, see text). TRPV6 is a duodenal epithelial Ca2+ channel
(EcaC-2)/calcium transporter (CaT1) displaying ankyrin
repeats towards the N-terminus.
phosphatidylinositol 4,5-bisphosphate (15, 16). Conserved molecular domains in all members of the TRP
family include ankyrin-like repeats near the N- terminus and a “TRP domain” at the C- terminus, which is a
highly conserved 25-amino acid stretch with still unknown functions (Fig. 1). At least one member of the
superfamily, TRPM5, displays voltage modulation,
despite the general absence of positively charged
amino acid residues in the 4th transmembrane segment, a typical feature of voltage-gated cation channels (17). Members of the TRP superfamily are fairly
ubiquitous and display a highly conserved structure
throughout the evolutionary path, serving a variety of
functions in several tissues, as listed in Table I (4, 11).
The central nervous system and peripheral sensing apparatuses are the main areas of TRP channel distribution. Nevertheless, the list of tissues expressing one or
more members of the superfamily is continuously expanding, as are their proposed functions. The early
concept of TRP as signaling molecules has evolved into that of multifunctional ion channels, also responsible for the bulk transport of electrolytes by specialized
epithelia (kidney, intestine) (6).
TRP CHANNELS AND TRANSMEMBRANE CA2+ SIGNALING
The involvement of TRP proteins in capacitative Ca2+
influx has been definitively demonstrated almost 10
Menè
TABLE I - PROPOSED FUNCTIONS OF MEMBERS OF THE SEVEN MAJOR KNOWN TRP CHANNEL SUBFAMILIES IN
VARIOUS SPECIES
TRPA (Ankyrin)
1
hearing in vertebrates
TRPC (Canonical)
1
2
3
4
5
6
7
sperm acrosome reaction, pheromone sensing
neurodifferentiation, synaptic development
vasorelaxation, microvascular permeability
vascular tone regulation
slit diaphragm/podocyte foot processes, structural
TRPM (Melastatin)
TRPML (Mucolipin)
1
2
3
4
5
6
7
8
melanoma tumor suppressor
redox-sensing, oxidative stress-induced apoptosis
1
2
3
mucolipidosis
cation selective channel
taste cells
familial hypomagnesemia
cell survival, proliferation
thermal sensing, tumor marker
TRPN (NOMP), TRPL, Drosophila TRP
phototransduction (insect), mechanosensation
TRPP (Polycystin)
1
2
3
5
autosomic dominant polycystic kidney disease (ADPKD)
ADPKD left-right asymmetry in embryogenesis
ADPKD
ADPKD
TRPV (Vanilloid)
1
2
3
4
5
6
OSM-9
nociception
nociception
nociception
hearing, osmotic sensing
Ca2+ transport, kidney tubules
Ca2+ transport, duodenum
years ago (14, 18). The process accounts for the ability of various stimuli of the discharge of intracellularly
stored Ca2+ (namely all agents that trigger phospholipase C-γ-mediated breakdown of phosphoinositides,
releasing inositol (1, 4, 5)-trisphosphate, InsP3) to activate an inward Ca2+ conductance that refills the
stores and maintains a persistent elevation of [Ca2+]i
(2, 16). This relatively non-selective influx pathway is
currently known as store-operated Ca 2+ channel
(SOC) or ICRAC (intracellular Ca2+ release-activated
Ca2+ influx channel) (1, 2, 5, 7). Some controversy exists in the literature concerning the definition of the
channel as a receptor-operated channel (ROC). Such
structures should involve receptors releasing InsP3 upon direct binding of a ligand, with a possible intermediation of G-proteins. InsP3 itself apparently binds to a
receptor expressed on Ca2+ stores, such as the endoor sarcoplasmic reticulum (also called “calciosomes”),
and possibly other organelles (7, 14). There seems to
be no direct binding of extracellular ligands to the
TRP channel, whose operation seems instead controlled by calmodulin/InsP 3 or protein kinases.
Therefore, it seems more appropriate to consider it as
a SOC, with Ca2+ acting as a second messenger, perhaps in concert with another store-associated, simultaneously released, putative signaling molecule (5, 7,
14). Cells from genetically engineered TRP-null mutants display minimal or no capacitative Ca2+ influx;
on the other hand, it has been possible to express Ca2+
currents in Xenopus oocytes by transfecting TRP homologues (5, 8, 14). Again, functional behavior as
ROC or SOC can also depend on the different subunits assembled to form the native channel (6).
In the kidney, there is extensive evidence of SOC
activity, as revealed by our own continuous fluorescence monitoring of [Ca2+]i in cultured rat and human smooth muscle-like glomerular mesangial cells
(19-21). These and other experiments in renal cells
23
TRP channels and calcium in the kidney
occurs when CaCl2 is added extracellularly. Thirdly,
releasing intracellular stores by pharmacologic
means, i.e. by any of the above-mentioned vasoconstrictors or bypassing InsP3-coupled receptors with the
sarcoplasmic reticulum Ca 2+-ATPase (SERCA) inhibitor, thapsigargin, potently enhances Ca2+ influx
(Fig. 2, panel C).
These SOC features seem quite suited for the “tonic”
regulation of contractile cell activity, since they grant a
constant influx of Ca2+, amplifying the effects of rapid
spikes of [Ca2+]i induced by vasoconstrictors (1, 3, 7).
Therefore, intermittent ANG II generation could produce long-lasting contraction of the glomerular
microcirculation, in turn critical for the so-called
autoregulation of renal blood flow. The issue is also
relevant to systemic circulation and to other vascular
districts, since mesangial cells can be considered vascular SMC (VSMC) of the glomerulus (23, 24). Both
cardiac myocytes and pulmonary artery SMC display
fully functional TRPC isoforms (25, 26). In cardiac
myocytes, gene knock-out of SERCA pumps (duplicating the effects of thapsigargin) translates into TRPC4
and -5 upregulation (27).
Fig. 2 - Evidence for capacitative Ca2+ influx through storeoperated Ca2+ channels in cultured human glomerular mesangial cells (HMC). Panel A, a [Ca2+]i transient induced by 1
uM angiotensin II (ANG II) in the presence (upper trace) or absence of extracellular Ca2+ in the bathing media (Ca2+-free).
Note the disappearance of the persistent [Ca2+]i elevation of
lesser amplitude in the absence of external Ca2+. B, Ca2+ influx upon previous discharge of intracellular Ca2+ stores by
switching media to a Ca2+-free solution. C, thapsigargin (TPS,
0.1 mM), a SERCA inhibitor, transiently increases [Ca2+]i in
cells held in Ca2+-free solutions by releasing intracellular stores; this potentiates subsequent Ca2+ influx once 1-10 mM
Ca2+ (as CaCl2) is added (compare amplitude of the [Ca2+]i responses with panel B). Similar effects can be obtained with
ANG II or other receptor-mediated vasoconstrictors (not
shown). Fluorescence monitoring of fura 2-loaded monolayers of HMC, alternate excitation/emission wavelengths
340/380 and 500 nm, respectively.
have clearly shown that releasing intracellularly stored
Ca2+ through receptor-operated and receptor-independent mechanisms promotes subsequent Ca2+ influx (9, 19-22). This is illustrated by three lines of evidence, summarized by the representative tracings in
Figure 2. First, conventional phospholipase C agonists
(angiotensin II (ANG II), vasopressin and thromboxane A2) transiently increase [Ca2+]I; this initial “spike”
is followed by the sustained elevation of [Ca2+]i only if
the cells are bathed by media containing extracellular
Ca2+, but not in Ca2+-free media. Secondly, holding
the cells in a Ca2+-free solution is followed by a reduction in baseline [Ca2+]i. This protocol quickly depletes
the intracellular stores, in an attempt to balance the
outward Ca2+ flow down a reversed transmembrane
gradient. A substantial, progressive influx of Ca2+ then
24
TUBULAR EPITHELIAL CA2+ AND MG2+ TRANSPORT
THROUGH TRP CHANNELS
Recent studies clarified that TRP do not only exist in
most cell lines as a sensing/signaling apparatus, but
also serve as classical ports for transepithelial Ca2+,
Mg2+ (and perhaps other ions) fluxes. TRPV5 cloning
from vitamin D-responsive rabbit tubular epithelial
cells, and the cloning of TRPV6 (which shares a 75%
homology with the 5 isoform of subfamily V) from rat
duodenum suggests that these channels are responsible for vitamin D-stimulated Ca2+ absorption in the
distal nephron and in enterocytes, respectively (9, 10,
28) (Fig. 1). They have been previously referred to as
epithelial Ca2+ channels 1 and 2 (EcaC1, EcaC2).
Notably, TRPV5 and -6 tissue expression seems under
the transcriptional control of 1,25 (OH)2D3, estrogens
and plasma Ca2+ levels, consistent with a candidate
role in divalent ion homeostasis at the whole body level (9, 10, 28). In the kidney, the parallel activity of a
Na+/Ca2+ exchanger and Ca2+-ATPase of tubular cells
appears to maintain the cytosolic inward gradient supporting passive reabsorption of filtered Ca2+ through
apical TRPV6 channels in distal convoluted tubules
(29). This isoform is also expressed in the medullary
collecting tubule, a segment apparently not involved
in Ca2+ reabsorption (30). TRPV5 and -6 also form
multimers in the distal convoluted tubule. A recent report by Hoenderop et al employed genetic ablation of
TRPV5 in the distal convolute tubule of the murine
nephron, where a substantial amount of Ca2+ reab-
Menè
sorption takes place (10). These TRPV5-null mice
failed to reabsorb Ca2+, with resulting hypercalciuria
and polyuria, leading to altered bone mineral density,
elevated circulating 1,25-(OH)2D3 levels and skeletal
abnormalities (10). The observation seems relevant to
the pathogenesis of a number of human disorders
linked to hypercalciuria, ranging from idiopathic
hypercalciuria to kidney stones to various forms of
nephrocalcinosis, such as the medullary sponge kidney. Even osteoporosis has been suggested to result
from age- or hormonal-dependent TRPV5/-6 dysregulation (10).
TRPM6 and TRPM7, among the eight members of the
melastatin subfamily of TRP channels, are currently
believed responsible for epithelial Mg 2+ transport
(Tab. I, Fig. 1). TRPM6 mutations have been linked to
hereditary hypomagnesemia, a syndrome also characterized by secondary hypocalcemia. The unique atypical kinase activity exhibited at the C-terminus by both
TRPM channels has suggested the use of the term
“chanzymes” to describe non-conventional channel
proteins, endowed with dual functions (31).
TRP CHANNELS AND RENAL CYSTIC DISEASES
The appreciation that TRPC are integral components
of the luminal plasma membrane of tubular epithelial
cells has led to the evaluation of other possible roles of
these molecules. Epithelial cell cyst formation in autosomic dominant polycystic kidney disease (ADPKD)
has recently been linked to the PKD2 gene product, a
TRP Ca2+-permeable, non-selective channel protein of
the P subfamily, isoforms 1-5 (6, 11, 12). TRPP2 shares
25% amino acid identity with TRPC3 and -6 proteins,
at the level of the transmembrane spanning segments
IV-VI. The homologues TRPP3 and -5 are reportedly
not mutated in ADPKD. On the other hand, TRPP1
corresponding to PKD1 is a non-channel, larger
polypeptide with 11 transmembrane-spanning regions, which can complex and regulate PKD2. It has
recently been suggested that this protein, expressed
on a restricted area next to the basal body/centrosome
area of the cilium displayed by many tubular cells,
serves as a Ca2+ gating mechanism activated by the
bending of the cilium under the luminal flow (32).
The stimulation of cilia in cultured epithelial cells exposed to a flux of bathing media results in Ca2+ entry
(33). On the other hand, PKD1-null or cells lacking
the cilium itself display reduced Ca2+ responses upon
flow exposure; similarly, blocking Abs to PKD1 or
PKD2 impair Ca2+ influx in tubular epithelial cells
(32-34). Consistent with the concept of TRP-related
ciliary protein defects in ADPKD, the Tg737orpk mouse,
a recently developed animal model, displays increased
ciliary PKD2 levels (35).
Therefore, defective sensing of transepithelial flow
could play a role in the formation and growth of cysts
in the kidney and perhaps other organs. Ciliar y
mechanosensing can also bear relevance to the embr yology and biology of other organisms such as
C. elegans, which possesses homologues of PKD1 and 2
(36). Recent development in the research on ciliary
proteins has led to the identification of a number of
other mutated components that could provide a
pathophysiologic basis for cystic kidney diseases. This
seems to be the case for 450 KDa PKHD1 or fibrocystin, defective in autosomic recessive polycystic
kidney disease, NPHP1 or nephrocystine, altered in
nephronophtysis, and BBS4-8, mutated in the BardetBiedl oro-facial-digital syndrome (37, 38).
TRP CHANNELS: LINKS TO ARTERIAL HYPERTENSION?
Following the characterization of TRPC as SOC in
most non-excitable cell types, recent studies link defective TRP activity to impaired vasorelaxation, as in
aortic rings or endothelial cells from TRPC4-/- null
mice (39). Interestingly, the phenomenon is associated with reduced nitric oxide synthesis and the resulting attenuation of agonist-induced, L-nitroargininesensitive vasorelaxation. In the same experimental
model, thrombin-induced microvascular permeability
is reportedly decreased, along with impaired endothelial cell motility and stress-fiber morphology (40).
This is further proof that TRP/SOC operation is implicated in VSMC contractility and/or endothelial
function, with potential links to arterial hypertension.
A role of TRPC6 in the control of vascular tone and,
hence, of BP is shown by studies on the Ca2+ currents
activated by α-adrenoceptors, and by the ability of
antisense oligodeoxynucleotides (ODNs) to TRPC6 to
reduce arterial smooth muscle depolarization and
constriction induced by elevated pressure in intact
cerebral arteries (41). Anti-TRPC6 ODNs also inhibit
a cation current involved in pressure-induced myogenic depolarization, similar to micromolar concentrations of gadolinium, a blocking substitute for
mono- or divalent cations (42).
Studies in VSMC cultures from SHR hypertensive/
WKY normotensive rats, point to differential regulation of TRP channel proteins and their induction by
vasoconstrictors, such as ANG II. TRPM7 content has
been reported to be lower in SHR cells compared to
their WKY counterparts, translating in decreased intracellular Mg2+, a divalent cation selectively internalized through this channel. TRPM6 is upregulated by
ANG II, while the vasoconstrictor failed to affect
TRPM7 levels in SHR-derived VSMC, resulting in reduced translocation of annexin-1, a specific TRPM-7
substrate involved in the enzymatic cascades of apop25
TRP channels and calcium in the kidney
tosis (43). This could affect the proliferation/apoptosis balance in VSMC, with implications for the cellular
composition of vessels in hypertensive rats (44). Moreover, regulation of the expression and/or operation of
TRP channels by ANG II is further evidence of their
implication in signal transduction for vasoconstrictors, partly through persistent Ca 2+ (and perhaps
Mg2+) inward currents following the initial release of
stored Ca2+.
Hyperexpression of TRPC 3 and -6 in VSMC from
patients with primar y pulmonar y hypertension
could indicate a pathogenetic role of these channels
in this setting (26, 42). Since systemic, “essential”
arterial hypertension is often associated with
increased sensitivity to vasoconstrictors, and altered
[Ca 2+] i responses have been described in animal
models and human hypertension, there is a potential for TRPC to be involved in this area as well.
Moreover, VSMC proliferation is sensitive to [Ca2+]i,
with impaired cell growth by the removal of extracellular Ca2+ or the blockade of voltage-gated Ca2+
entry. Increased [Ca2+]i appears instead to promote
cell cycling and gene transcription, a mechanism
that can apply to ciliary defects leading to cyst formation in ADPKD (32-35, 44). The correlation between TRPC6 expression and VSMC entry in the S
and G2/M phases of the cell cycle shown by Yu et al
(26) points to capacitative Ca2+ influx as one mechanism controlling hypertrophy of VSMC and perhaps
myocardial cells, relevant to pulmonar y and systemic hypertension (26, 39, 40). The role of SOC in
providing sustained [Ca2+]i in VSMC isolated from
human pulmonary arteries is backed by and possibly
functionally coupled to a Na+/Ca2+ exchanger (25).
TRP could be implicated in other cellular functions
relevant to vascular disease, atherosclerosis and
hypertension. Their involvement in apoptosis and
cellular proliferation ranges from the upregulation
of TRPM members (melastatin) in tumors (45, 46)
to enhanced apoptosis in response to reactive oxygen species (ROS), as in the case of TRPM2, regulated by H2O2 , ADP-ribose, and tumor necrosis factor alpha (TNF-α) (47, 48) (Fig. 1). TRP Ca2+ channels have been shown to serve as redox sensors in
the vascular endothelium (47). TRPC3 expression
mediates the nitric oxide sensitivity of SOC. Overexpression in HEK293 cells confirmed that TRPC3 and
TRPC4 have features of redox sensitive cation channels (48, 49). ROS-activated protein tyrosine phosphorylation and phospholipase C are involved in redox activation of TRPC3. Furthermore, oxidative
stress-induced disruption of caveolin 1-rich lipid raft
domains interferes with functional TRPC channels,
contributing to redox modulation of TRP proteins
and to oxidative stress-induced changes in cellular
Ca2+ signaling (48). Apoptosis can be pharmacologi26
cally modulated through the depression or the activation of Ca 2+ currents (50). Pathological redox
states can promote cell death through TRP channelmediated Ca2+ fluxes, as shown for TRPM2 (47, 48).
This protein, already labeled LTRPC2 or TRPC7
(Fig. 1) contains an ADP-ribose pyrophosphatase
domain, which catalyzes the hydrolysis of nucleoside
diphosphates. As mentioned earlier, this is an example of a subfamily of channels endowed with enzymatic activity, the so-called chanzymes. The Nudix
hydrolase domain at the C-terminus of TRPM2
serves as a binding site for nucleotides (ADP-ribose,
NAD), which then promote Ca2+ entry and apoptosis of cells exposed to ROS and/or to a high redox
microenvironment (47-49). In summary, TRP channels are implicated at various levels at the vascular
cell/circulating inflammatory cell interface, where
oxidative stress, leukocyte activation and disorderly
proliferation of endothelial cells are associated with
atherosclerotic plaques, often in the context of arterial hypertension (51, 52).
TRP CHANNELS, PODOCYTES AND FOCAL GLOMERULOSCLEROSIS
One recent advance in the pathophysiologic roles of
TRP channels is the parallel description by two
independent research groups of a mutation of the
TRPC6 gene on chromosome 11q in six families with
autosomal dominant focal segmental glomerulosclerosis (FSGS) (53, 54). TRPC6 is apparently expressed in the foot processes of podocytes, which are
severely effaced in this disorder, a lesion responsible
for massive proteinuria with resulting nephrotic syndrome. Mutation is located at the level of proline
112, replaced by glutamine in one of three ankyrin
repeats. This breakthrough discovery, if confirmed,
will shed new light on the role of ion channels in
podocyte physiology, as TRPC6 protein displays altered intracellular distribution in podocytes from
subjects with FSGS, along with increased current
amplitudes and ANG II-induced [Ca2+]i signals (53,
54). TRPC6 could be involved in guiding slit diaphragm assembly around the foot processes, and
perhaps control podocyte proliferation, apoptosis or
other cellular functions through enhanced Ca2+ signaling (55, 56). These data, taken together with recent evidence of a role of mutated podocyte proteins in other congenital forms of nephrotic syndrome, as in the case of the nephrin-podocin complex, could contribute to a new approach in the
study of proteinuric glomerular diseases (55). At the
same time, they provide further support to the concept of a structural and functional role of TRP channels well beyond ion gating and signal transduction.
Menè
CONCLUSIONS
The identification and the characterization of TRP
cation channels is one of the most exciting recent
developments of research concerning signaling and
ion transport. These cellular processes are becoming
increasingly linked by the discovery of multifunctional proteins that assemble in a variety of combinations,
according to the required functions. The involvement
of Ca2+ in intracellular signaling has been known for
almost 20 yrs. It is now becoming apparent that the
same mechanisms that allow instantaneous firing of
action potentials in the visual apparatus of insects, also serve as sensors of luminal flow in renal tubules,
and at the same time as regulators of foot process morphology in podocytes or ion transporters in the distal
nephron. This is remarkable in evolutionary terms,
and constitutes evidence of an additional, novel role
of ion carriers as sensors of the surrounding environment (57, 58).
TRP are also apparently implicated in the pathogenesis of a host of long-known genetic and acquired
diseases. The development of pharmacologic inhibitors of non-voltage gated Ca2+ entry (59) is underway, with promising potential in the treatment of cardiovascular and renal disorders ranging from arrhythmias to hypertension, from mineral and electrolyte
disturbances to nephrolithiasis and to hereditary cystic diseases.
ACKNOWLEDGEMENTS
This work has been supported by research grants from the Ministry of
the University of Italy (MIUR - Ricerche di Facoltà, Ricerche di Ateneo).
Address for correspondence:
Paolo Menè, M.D.
U.O.C. Nefrologia
Azienda Ospedaliera Sant’ Andrea
Via di Grottarossa 1035-1039
00189 Rome, Italy
Paolo.Mene@uniroma1.it
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Received: September 25, 2005
Revised: November 28, 2005
Accepted: December 19, 2005
© Società Italiana di Nefrologia
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