Article

Caenorhabditis elegans, a model organism for kidney research: From cilia to mechanosensation and longevity

Renal Division, Department of Medicine and Centre for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Current opinion in nephrology and hypertension (Impact Factor: 3.96). 07/2011; 20(4):400-8. DOI: 10.1097/MNH.0b013e3283471a22
Source: PubMed
ABSTRACT
The introduction of Caenorhabditis elegans by Sydney Brenner to study 'how genes might specify the complex structures found in higher organisms' revolutionized molecular and developmental biology and pioneered a new research area to study organ development and cellular differentiation with this model organism. Here, we review the role of the nematode in renal research and discuss future perspectives for its use in molecular nephrology.
Although C. elegans does not possess an excretory system comparable with the mammalian kidney, various studies have demonstrated the conserved functional role of kidney disease genes in C. elegans. The finding that cystic kidney diseases can be considered ciliopathies is based to a great extent on research studying their homologues in the nematode's ciliated neurons. Moreover, proteins of the kidney filtration barrier play important roles in both correct synapse formation, mechanosensation and signal transduction in the nematode. Intriguingly, the renal cell carcinoma disease gene product von-Hippel-Lindau protein was shown to regulate lifespan in the nematode. Last but not least, the worm's excretory system itself expresses genes involved in electrolyte and osmotic homeostasis and may serve as a valuable tool to study these processes on a molecular level.
C. elegans has proven to be an incredibly powerful tool in studying various aspects of renal function, development and disease and will certainly continue to do so in the future.

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Caenorhabditis elegans, a model organism for kidney research:
from cilia to mechanosensation and longevity
Roman-Ulrich Mu
¨
ller
a,b
, Sibylle Zank
a
, Francesca Fabretti
a
and
Thomas Benzing
a,b
Introduction
Caenorhabditis elegans, a free-living nematode of about
1 mm length, had not come to scientific attention until
Sidney Brenner recognized its enormous potential in
the 1960s [1

]. With adult hermaphrodites being com-
posed of a defined number of 959 in males 1031
cells and its short lifecycle, it turned out to be the ideal
tool to study the genetic basis of wiring the nervous
system and cell d ifferentia tion (Fig. 1a) [2]. The intro-
duction of the nematode into modern molecular biology
and the description of cell lineage development
and apoptotic cell death led to the award of the Nobel
prize for Sidney Brenner, Robert Horvitz and John
Sulston in 2002. The discovery of gene silencing by
double-stranded RNA using C. elegans as a model
culminated in the same prize for Andrew Fire and
Craig Mello in 2006. Moreover, the introduction of
green fluorescent protein as a tool to monitor protein
expression and cell movements with the help of
C. elegans by Martin Chalfie revolutionized cell and
developmental biology and was also rewarded with
theNobelprizein2008.
Since the early Brenner work, the community of labora-
tories employing this fascinating model organism has
been growing rapidly, also including groups studying
the function of renal disease genes. Genetic manipulation
such as the creation of knockout and transgenic lines
is quite simple in the nematode allowing for genetic
screening protocols in defined phenotypes. Furthermore,
C. elegans was not only the first animal in whi ch micro-
RNAs could be described as functional regulators of gene
expression [3], yet it can be easily manipulated using
RNA interference [4]. The nematode can be grown on
bacterial lawns of, for example, Escherichia coli bacteria
expressing double-stranded RNA targeting specific
C. elegans transcripts, which can be used to knockdown
genes in this model organism in a very simple and time-
saving fashion [5].
a
Renal Division, Department of Medicine and Centre
for Molecular Medicine and
b
Cologne Excellence
Cluster on Cellular Stress Responses in Aging-
Associated Diseases, University of Cologne, Cologne,
Germany
Correspondence to Thomas Benzing, Renal Division,
Department of Medicine, University of Cologne,
Kerpener Street 62, 50937 Cologne, Germany
Tel: +49 221 478 4480; fax: +49 221 478 5959;
e-mail: thomas.benzing@uk-koeln.de
Current Opinion in Nephrology and
Hypertension 2011, 20:400408
Purpose of review
The introduction of Caenorhabditis elegans by Sydney Brenner to study ‘how genes
might specify the complex structures found in higher organisms’ revolutionized
molecular and developmental biology and pioneered a new research area to study organ
development and cellular differentiation with this model organism. Here, we review the
role of the nematode in renal research and discuss future perspectives for its use in
molecular nephrology.
Recent findings
Although C. elegans does not possess an excretory system comparable with the
mammalian kidney, various studies have demonstrated the conserved functional role of
kidney disease genes in C. elegans. The finding that cystic kidney diseases can be
considered ciliopathies is based to a great extent on research studying their
homologues in the nematode’s ciliated neurons. Moreover, proteins of the kidney
filtration barrier play important roles in both correct synapse formation,
mechanosensation and signal transduction in the nematode. Intriguingly, the renal cell
carcinoma disease gene product von-HippelLindau protein was shown to regulate
lifespan in the nematode. Last but not least, the worm’s excretory system itself
expresses genes involved in electrolyte and osmotic homeostasis and may serve as a
valuable tool to study these processes on a molecular level.
Summary
C. elegans has proven to be an incredibly powerful tool in studying various aspects of
renal function, development and disease and will certainly continue to do so in the future.
Keywords
aging, Caenorhabditis elegans, cilia, kidney, slit diaphragm
Curr Opin Nephrol Hypertens 20:400408
ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1062-4821
1062-4821 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MNH.0b013e3283471a22
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In 1999, a landmark publicatio n describing the expres-
sion of polycystin-1 and polycystin-2 homologues
LOV-1 and PKD-2 in male ciliated neurons and the
functionofLOV-1inmalematingbehaviorwasthefirst
indication for kidney researchers that C. elegans was going
to be a promising tool in their research [6]. This view
was soon to be reinforced by further s tudies on both
these two and other cystic kidney disease genes and
could be extended to the renal slit diaphragm through
functional characterization of SYG-1 a Neph homo-
logue in 2003 [7].
Phenotyping ciliary defects in Caenorhabditis
elegans
The only group of ciliated cells in the nematode is
unlike many other animals a subset of sensory neurons.
Sixty out of 302 neurons are ciliated in C. elegans adult
hermaphrodites, providing the opportunity to study the
function of ciliary proteins. Males possess 52 additional
ciliated sensory neurons, which are involved in male-
mating behavior [8].
There are a couple of further phenotypic readouts which
are generally used to screen for ciliary defects. Both
chemotaxis and osmotic avoidance are affected in ciliary
mutants. The uptake of a number of lipophilic dyes such
as DiO, DiI and FITC by ciliated neurons depends on
intact intraflagellar transport, the disruption of which
leads to the so-called dye-filling phenotype (Fig. 1b).
Furthermore, velocity and efficiency of intraflagellar
transport can be measured in C. elegans using fluorescent
markers of intraflagellar transport (IFT) proteins and
ciliary structure may be examined through both immuno-
fluorescent marker proteins and electron microscopy.
Caenorhabditis elegans mating and
autosomal dominant polycystic kidney
disease
The aforementioned study by Paul Sternberg and
Maureen Barr first identified the C. elegans homologues
of polycystin-1 and polycystin-2 the mutation of which
is the cause of autosomal dominant polycystic kidney
disease LOV-1 and PKD-2 to be expressed in male-
specific ciliated neurons [6]. LOV-1 and PKD-2 act in the
same ciliary pathway in C. elegans and their mutation leads
to defects in two steps of male mating behavior
response behavior and vulva location yet they are
not required for ciliogenesis [9]. Subcellul ar localization
studies in C. elegans were employed to identify domain
Caenorhabditis elegans in kidney research Muller et al. 401
Key points
Numerous human kidney disease genes, involved
in cystic kidney disease, the development of
proteinuria or renal cell carcinoma, are highly con-
served and have homologues with similar molecular
function in Caenorhabditis elegans.
Through defined phenotypes in ciliary function,
mechanosensation, synaptogenesis and lifespan
regulation, C. elegans serves as a versatile model
organism in basic renal research.
The nematode excretory system may serve as a
model of renal physiology and disorder especially
regarding channel and transporter function.
Molecular and developmental biologists working
with C. elegans and nephrologists should team up
to take advantage of these tools and obtain new
knowledge that will help to understand clinically
relevant kidney disorders and their molecular
disease mechanisms.
Figure 1 Caenorhabditis elegans as a model of ciliary function
(a) Upper tile Nomarski image of a C. elegans adult worm; lower tile schematic view of C. elegans (adapted and reprinted with permission from [2]); (b)
dye-filling experiment using DiO, left panel showing intact dye filling of head (upper image) and tail (lower image) ciliated neurons in a wild-type N2
worm, right panel showing abrogated dye filling in an osm-5 mutant worm; the image was overexposed in order to exclude any uptake of the dye (original
image).
Page 2
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requirements and interaction with other proteins essen-
tial for ciliary localization and signaling regulation of
polycystins [1012]. Recently, CWP-5 a single-pass
transmembrane p rotein with ci liary loc aliza tion i n male
neurons was identified as a new genetic interactor of
the p olyc yst ins in C. elegans [13]. cwp-5 mutant worms
show an impaired male response behavior, a phenotype
that does not get more severe when combined with
lov-1; pkd-2 double knockout alleles. Interestingly, the
respective single knockout of the two polycystins had
been shown to have a more severe phenotype than the
double knockout suggesting a potential inhibitory
function on cilia sensory function of the remaining
polycystin. Loss of cwp-5 significantly deteriorates male
response behavior in a lov-1 or pkd-2 loss-of -functi on
background implying CWP-5 modifies this inhibitory
function of polycystins. No functional homologue
of cwp-5 has been identified in mammals so far, thus
future studies will be required to understand whether
this functional interaction may play a role as a modifier
of autosomal dominant polycystic kidney disease
(ADPKD).
Autosomal recessive polycystic kidney
disease and the worm
Osm-5, the homologue of the mouse autosomal recessive
polycystic kidney disease gene tg737, localizes to
the cilia of sensory neurons and is essential for correct
ciliary targeting of LOV-1 and PKD-2 in male-specific
neurons. Because of its function in all sensory neurons,
osm-5 mutant worms show not only mating deficiencies
but also an array of ciliary phenotypes such as defects
in osm otic avoidance, chemotaxis and dye filling ( Fig. 1).
In contrast to the conserved function of tg737,thereare
no C. elegans homologues of fibrocystin the gene
mutated in human autosomal recessive polycystic
kidney disease and cystin, which is disrupted in the
cpk mouse model of autosomal recessive polycystic
kidney disease.
Nematode cilia and juvenile cystic kidney
diseases
An array of genes involved in congenital syndromes
that go along with juvenile cystic kidney diseases
such as juvenile nephronophthisis (NHPH), Bardet
Biedl syndrome (BBS), MeckelGruber syndrome
(MKS) and Joubert syndrome (JBTS) are conserved
in C. elegans (Table 1) [6,9,1421,22
,23
,2429

].
Most of the early data on these proteins have been
reviewed elsewhere, so we will focus on the more
recent reports in this review [30,31]. NPH-1 and
NPH-4 are expressed in a subset of sensory neurons
where the protein products localize to cilia at which
the single mutants show only very mild phenotypes,
while the nph-1; nph-4 double mutants have both male
mating defects and ultrastructural axonemal defects as
shown by electron microscopy studies. In contrast to
osm-5 mutant worms, these strains show intact osmotic
avoidance, dye filling and chemotaxis [1719].
An identifying feature of MKS-1, one of six gene products
that are mutated in MKS, is the so-called B9-domain.
Combined knockout of all B9-domain proteins (XBX-7,
TZA-1 and TZA-2) in C. elegans results in impaired
foraging and increased lifespan due to altered insulin
signaling, a pathway that is largely mediated by ciliated
neurons. Moreover, crossing with nph-4 or nph-1 mutants
leads to altered cilia morphology and dye-filling defects,
indicating potential functional redundancy of these genes
[20,21]. C. elegans mks-3 localizes to the base of cilia and
mutants form cilia that are increased in length, mimicking
the rodent knockout phenotype. nph-4 ; mks-3 double
mutants show greatly augmented ciliary phenotypes
compared with the respective single mutants implying
a highly synergistic roles of these tw o proteins in cilia
formation [32
]. ARL-13 a small GTPase mutated in
JBTS localizes to proximal regions of the ciliary axo-
neme and interacts genetically with ciliary transport-
associated genes [22
]. ARL-13 mutants show defects
in cilium morphology and ultrastructure, as well as
defects in ciliary protein localization and transport.
Depletion of another small GTPase ARL-3 rescues
the arl-13 mutant phenotype through an HDAC6 dea-
cetylase-dependent pathway [23
]. BBS is another her-
editary disorder featuring juvenile cyst ic kidney disease
among other defects and is caused by the mutation of the
so-called BBS genes, the protein products of which
localize to the base of sensory cilia in C. elegans. Their
transcription is mediated by DAF-19, an RFX-transcrip-
tion factor that regulates an abundance of genes
expressed in sensory cilia and is essential for cilia for-
mation. Apart from BBS proteins, DAF-19 drives the
expression of a number of additional ciliary transcripts,
a fact that was exploited in bioinformatic screens for new
ciliary proteins [24,33]. BBS-7 and BBS-8 could be shown
to be necessary for correct localization of IFT proteins;
consequently, their mutation leads to both functional and
structural ciliary defects [2528,29

,30,31,32
,3337].
Interestingly, BBS-1 was linked to the regulation of fat
storage in the nematode linking the model organism even
closer to the human syndrome, which goes along with
severe obesity [26]. Furthermore, it was possible to
recapitulate the thermosensati on deficient phenotype
of bbs1 or bbs4 knockout mice in C. elegans, which here
is most likely mediated through the interaction of BBS
proteins with OSM-9, a polymodal sensory channel
protein and a functional homolog of TRPV1 or TRPV4
[27]. More recent evidence suggests that BBS proteins
together with RAB-8/10 interact with the sensory signal-
ing pathway to regulate cilia structure [38]. Interestingly,
402 Renal pathophysiology
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Caenorhabditis elegans in kidney research Muller et al. 403
Table 1 Cystic kidney disease genes conserved in Caenorhabditis elegans are listed with their homologues and corresponding phenotypes (original table)
Homo sapiens Human disease Caenorhabditis elegans Phenotype/function
BardetBiedl syndrome 1 (BBS1) BBS bbs-1; BBS protein Increased fat storage [26]
BardetBiedl syndrome 2 (BBS2) BBS bbs-2; BBS syndrome protein Localizes to the base of the cilium [25]
ARL6; ADP-ribosylation factor-like 6 BBS arl-6; ARF-like Ciliary localization (Fan et al. [15])
BardetBiedl syndrome 4 (BBS4) BBS F58A4.14 hypothetical protein Not studied
BardetBiedl syndrome 5 (BBS5) BBS bbs-5; BBS protein Localizes to the base of the cilium (Li et al. [14])
BardetBiedl syndrome 7 (BBS7) BBS osm-12; OSMotic avoidance abnormal Ciliary defect [25], deficient thermotaxis [27]
TTC8; tetratricopeptide repeat domain 8 BBS bbs-8; BBS protein Ciliary defect [25], deficient thermotaxis [27]
BardetBiedl syndrome 9 (BBS9) BBS bbs-9; BBS protein Dye-filling defects [24]
MeckelGruber syndrome 1 (MKS1) MKS/BBS mks-1 (xbx-7); MKS homolog; mksr-1
(tza-1); MKS1 related; mksr-2 (tza-2);
MKS2 related
Interaction with nph-pathway to maintain ciliary
structure and function [20,21]
Transmembrane protein 67 (TMEM67) MKS/JBTS/NPHP mks-3 (F35D2.4) Cilia that are increased in length (Williams et al. [16])
RPGRIP1L; RPGRIP1-like MKS/JBTS/NPHP C09G5.8; hypothetical protein Not studied
Nephronophthisis 1 (NPHP1) (juvenile) NPHP/JBTS/Senior-Loken
syndrome
nph-1; NPHP (human kidney
disease) homolog
Chemoattraction, male mating behavior, foraging
and lifespan [1720]
Inversin (INVS) NPHP mlt-4 molting defective Not studied
Nephronophthisis 4 (NPHP4) (juvenile) NPHP/Senior-Loken syndrome nph-4; NPHP (human kidney
disease) homolog
Chemoattraction, man-mating behavior, foraging behavior,
and lifespan (see NPHP1)
NEK8; NIMA (never in mitosis gene a)-
related kinase 8
NPHP nekl-1; NEK (Never in mitosis kinase) Like Not studied
ARL13B; ADP-ribosylation factor-like13B JBTS arl-13; ARF-like Intraflagellar transport defects [22
,23
]
Polycystic kidney disease 1 (PKD1) Autosomal dominant polycystic
kidney disease
lov-1; location of vulva defective 1 Male mating defects [6]
Polycystic kidney disease 2 (PKD2) Autosomal dominant polycystic
kidney disease
pkd-2; human PKD2 related Male mating defects [9]
von HippelLindau (VHL) tumor suppressor VHL syndrome vhl-1; VHL tumor suppressor homolog Extended lifespan [28,29

]
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a phylogenetic analysis identifying an ancestral centriolar
inventory showed BBS proteins to be absent from
organisms that dispose of cilia only for the purpose of
motility, linking the BBSome even more closely to
sensory functions [39
].
The excretory system of Caenorhabditis
elegans
Albeit lacking a filtration barri er comparable with the
mammalian kidney filter, C. elegans is equipped with a
specialized excretory system. This system consists of
four cells: the pore cell, the duct cell, the canal or
excretory cell forming an intracellular tubule, and a
fusedpairofglandcells[40].First insight into a function
of this system in osmoregulation arose in 1984, when
Nelson and Riddle [41] showed that laser ablation led to
a fluid influx and premature death of the animal w ithin
several days. Excretion by the canal cell via the duct and
pore cells to the outside r esembles some aspects of the
excretory tasks of the mammalian kidney. As cysts are
epithelial lined, fluid-filled structures, it is doubtful that
the canal cell as a single cell can be seen as an appropriate
model to study cystic kidney disease even though
mutations in several genes like exc-1 to ex c-9 lead to
formation of cystic structures [42]. Nonetheless, the
description of further homologues and genes involved
in function and formation of the excretory system will
draw a line from the excretory system in C. elegans to the
mammalian kidney. Genes already known to be involved
in these processes include interesting candidates such a s
chloride channels of the CLIC-family, the HNF-4
homologue NHR-31 and the conserved interaction of
Klotho with the FGF-receptor [43,44,45
]. The POU-III
transcription factor CEH-6 controls the expression of a
wide number of transport and channel proteins in the
excretory system [46,47]. Knockout of the mammalian
homologue brn1 in mice leads to a severely retarded
development of Henle’s loop, the distal convoluted
tubule and the macula densa and death due to renal
failure [48].
Homologues of Nephrin and Neph in
Caenorhabditis elegans are involved in
synaptogenesis
Our knowledge on the function of the kidney filtration
barrier and the molecular composition of the slit dia-
phragm has increased dramatically during the last decade.
Soon after the characterization of Nephrin in 1998 by Karl
Tryggvason’s group, numerous additional proteins were
identified as part of the slit diaphragm protein super-
complex [49].
Nephrin and the members of the Neph family are highly
conserved throughout evolution. In C. elegans, SYG-1 and
SYG-2, the homologues of Neph1 and Nephrin, are
required for correct positioning of synaptic sites between
the hermaphrodite specific neuron (HSN) and its target
cells. During maturation, presynaptic sites are estab-
lished along the neuronal processes and subsequently
removed by ubiquitinylation [50]. Synaptic contact is
only established at sites at which a direct interaction
between SYG-1 and SYG-2 takes place [7,51] (Fig. 2).
Loss of SYG-1 or SYG-2 respectively leads to mislocali-
zation of the synaptic contacts, also the domain require-
ments of this functional interaction were examined in
C. elegans [52]. In 2010, Neumann-Haefelin et al. [53
]
reported that expression of mouse Neph13 partially
rescued the syg-1 mutant phenotype, thereby demonstrat-
ing that these cellular adhesion modules are functionally
conserved across species. Future studies in C. elegans will
404 Renal pathophysiology
Figure 2 Nephrin/Neph interactions direct synaptogenesis
(a) Schematic view of the SYG-1/SYG-2-mediated interaction of the hermaphrodite specific neuron (HSN) and the epithelial guidepost cell (original
image); (b) upper tiles fluorescent spots at the vulva of L4 larvae as labeled using a synaptobrevin-1::YFP reporter strain (kind gift from [48]) show the
localization of synapses formed by the HSN (white arrow); lower tiles the same reporter strain crossed into a syg-1 mutant showing dispersal of
synapses (gray arrow) to a region no longer limited to the vulva (white arrow), (original image).
Page 5
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
help to better unde rstand NephrinNeph-mediated cell
adhesion and signaling processes.
The slit diaphragm as a mechanosensor?
The complex organization of the slit diaphragm and the
mechanosensory machinery in C. elegans are closely
related. The gentle touch sen sor in C. elegans comprises
among others the PHB-domain protein MEC-2, the ion
channel MEC-4/10 and a tight anchoring to the cytoske-
leton. Similarly, the slit diaphragm contains the PHB
domain protein podocin, TRPC6 ion channels and a
strong connection to the cytoskeleton [54,55] (Fig. 3).
Both MEC-2 and podocin orchestrate the lipid environ-
ment of these proteinlipid supercomplexes by binding
cholesterol, thereby regulating the activity of MEC-4/10
or TRPC6 channels, respectively [55]. These results
imply that the slit diaphragm may represent a glomerular
mechanosensor that might regulate glomerular perfusion
and filtration. C. elegans provides the perfect tool to study
both lipid and protein modifiers of the function of this
signaling complex. Exertion of gentle touch to nose or tail
of the nematode and the consequent motor response can
be used to quantify activity of its mechanosensor [56].
Von-HippelLindau tumor suppressor protein
and lifespan regulation
C. elegans is one of the most important model organisms
regarding aging research due to its short lifecycle about
21 days at 208C and development from egg to adult in
about 3 days and simple genetic modification.
Probably the most active field during the last 2 years
regarding kidney proteins in C. elegans were studies on the
role of von-HippelLindau protein (pVHL) in lifespan
regulation.
Hereditary mutations in the von-HippelLindau (VHL)
gene cause the VHL syndrome; affected patients develop
both a variety of tumors and polycystic kidneys resem-
bling ADPKD. Sporadic mutations in the VHL gene are
observed in 80% of all cases of renal cell carcinoma
making it the most prominent renal tumor suppressor
protein.
The function of pVHL has been studied most exten-
sively in its role as the substrate-recognition subunit of an
E3-ubiquitin ligase mediating proteasomal degradation
Caenorhabditis elegans in kidney research Muller et al. 405
Figure 3 The slit diaphragm as a mechanosensor
(a) The left tile shows a schematic view of the protein complex at the renal slit diaphragm, the right tile shows the Caenorhabditis elegans
mechanosensor complex in comparison (updated from [52]); (b) immunofluorescence staining using a polyclonal anti-MEC-2 antibody (kind gift from
Martin Chalfie) shows a punctate pattern along the mechanosensory neurons PLML and ALML (original image).
Page 6
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of hypoxia-inducible factor 1a under normoxic con-
ditions. This pa thway is entirely conserved in C. elegans.
Other features of pVHL independent from its being part
of an E3-ubiquitin ligase comprise a role in microt ubule
stabilization and ciliogenesis, which explains the devel-
opment of polycystic kidneys in VHL patients [57].
Interestingly, in 2009, we and other groups were able
to show that loss of vhl-1 increases lifespan of the nema-
tode significantly [28,29

].
The elongation of lifespan was not mediated by insulin
signaling the most prominent longevity pathway yet
depended on the upregulation of hif-1. Resistance to both
to oxidative and proteotoxic stress are increased in these
mutant worms. Unsuspectedly, when worms are grown at
258C meaning heat stress for the nematode lifespan
extension could be mediated by loss of hif-1 as well, this
time through an insulin signaling-dependent pathway
[58,59,60
] (Fig. 4). Furthermore, it had been known
before that inhibition of respiration through genetic
modulation of the respiratory chain could increase life-
span, a phenomenon that has now been linked to
increased hif-1 activity as well [61
]. At first, it seems
peculiar that the loss of an important tumor suppressor
protein should increase lifespan. Yet an organism like C.
elegans with an extremely short lifespan and upon reach-
ing adulthood no replicating cells apart from the germline
does not have to deal with the problem of tumorigenesis.
In this context, tumo r suppressor proteins may actually
reduce cellular maintenance and stress resistance. This
hypothesis is reinforced by the fact that loss of the p53
homologue in C. elegans is able to confer lifespan exten-
sion as well [62]. Hence, it is intriguing to hypothesize the
existence of a fine-tuned balance between cellular resist-
ance/survival and tumor formation, which is regulated
through tumor suppressor proteins. This may in the
future provide the opportunity to induce stress resistance
through timely limited inhibition of tumor suppressor
proteins such as pVHL when patients are exposed to for
example ischemic stress while undergoing surgery or
contrast agent exposure.
Conclusion
C. elegans has become one of the most important model
organisms in molecular biology during the last decades.
Upon the identification of PKD-1 and PKD-2 homologues
in the nematode, nephrologists have become increasingly
aware of its potential leading to its use as a model for an
array of molecular pathways both in tubular cells and
podocytes. We are convinced that the next years will
reveal C. elegans to be an extremely useful tool for a
growing community of scientists studying renal function
and disease.
Acknowledgements
The authors thank Martin Chalfie for very fruitful discussions regarding
their C. elegans work; the anti-MEC-2 antibody was a kind gift from his
laboratory. Kang Shen generously provided us with the SNB-1::yfp
expressing reporter strains. The authors apologize to those colleagues
whose work could not be cited due to space limitations.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 440443).
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406 Renal pathophysiology
Figure 4 Von-HippelLindau protein in lifespan regulation
A schematic view of the interaction of VHL-1/HIF-1 with other longevity pathways; (a) 208C; (b) 258C (original image).
Page 7
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