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Department of Medicine, Division of Nephrology, University of Freiburg, D-79106 Freiburg, Germany
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The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that podocyte foot processes counteract the elastic force of the glomerular basement membrane and that vasoactive hormones may regulate the contractile state of their foot processes and thereby modulate the ultrafiltration coefficient Kf. Podocyte damage leads to proteinuria, and podocyte injury occurs in many glomerular diseases, which may progress to chronic renal failure. The understanding of the regulation of physiological properties of the podocyte and the mechanisms of its cellular response to injury may thus provide a clue to the understanding of the pathogenesis of proteinuria and glomerular diseases. In the past it was difficult to study cellular functions in this cell type, because of its unique anatomic location and the difficulty in characterizing podocytes in cell culture. However, recent advances in physiological, molecular biological, and cell culture techniques have increased the knowledge of the role of the podocyte in glomerular function. The present review attempts to outline new aspects of podocyte function in the glomerulum.
hormones; podocyte function; glomerulum
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PODOCYTES ARE HIGHLY SPECIALIZED cells, which form
multiple interdigitating foot processes. They are interconnected by
slit diaphragms and cover the exterior basement membrane surface of the
glomerular capillary. They stabilize glomerular architecture by
counteracting distensions of the glomerular basement membrane (35) and
maintain a large filtration surface through the slit diapgragms (19).
In this regard they are responsible for ~40% of the hydraulic
resistance of the filtration barrier (19). Podocyte foot processes
possess a contractile structure composed of actin, myosin, 
-actinin,
vinculin, and talin, which are connected to the glomerular basement
membrane at focal contacts by an 3
1-integrin complex (1, 18). The
contractile structures of the podocyte foot processes may respond to
vasoactive hormones and thereby modulate the ultrafiltration
coefficient Kf (18, 35). Podocytes contribute to
the specific size and charge characteristics of the glomerular
filtration barrier, and their damage leads to a retraction of their
foot processes and proteinuria (36, 46). They are the target of injury
in many glomerular diseases. Podocyte cell shape changes, including
retraction of foot processes and even a loss of podocytes, occur in
minimal-change nephropathy, membranous nephropathy, focal segmental
glomerulosclerosis (FSGS), chronic glomerulonephritis, and diabetic
nephropathy (29, 34, 45). Despite decades of research, the
physiological and molecular mechanisms of glomerular filtration and its
disturbances are hardly understood. An important step in understanding
the glomerular function and disease will therefore inhabit the
knowledge of the regulation of podocyte biology. The present review
sets out to focus on recent advances in the knowledge of podocyte function.
New Methodological Approaches for Studying Podocyte Function
Patch-clamp studies in podocytes of the intact glomerulum.
The three resident glomerular cell types, i. e., the podocyte, the
glomerular endothelial cell, and the mesangial cell form a complex
architecture. Because of their anatomic location it is difficult to
detect the particular glomerular cell type involved in a hormone
response. Most of the knowledge concerning the physiological function
of glomerular cells is based on results obtained from cultured cells.
However, the extrapolation of these data to the in vivo situation
appears difficult as cells often lose characteristic morphological and
functional features during culture. Also, the different glomerular cell
types might influence each other; i. e., there is probably
cross-communication between different glomerular cells. We have
recently developed a technique allowing the examination of
electrophysiological properties of podocytes in the glomerulum (20).
Figure 1 shows the procedure of the
preparation: isolated glomerula with an intact Bowman capsule were
placed into a bath chamber under an inverted microscope and immobilized
at the vascular pole by a pipette. After a short-time incubation with
collagenase, the Bowman capsule was stripped off with a pipette, and a
patch pipette was then placed onto a podocyte surface. After a gigaohm seal was achieved, the whole cell configuration was established and
membrane voltage and ion conductances of podocytes were measured. By
using this technique it was possible to investigate functional properties of podocytes in situ. However, the procedure is quite difficult, and only in ~3% of all experiments did we succeed in getting a stable whole cell configuration. In addition, the glomerulum collapses and the period of time between isolation of the glomerulum and successful experimentation is rather long after the Bowman capsule
is stripped off. Thus, although we have proven the morphological integrity of the podocytes by electromicroscopy, podocyte function could be altered by these factors (20). Some of the difficulties with
this technique could be overcome by using new technical approaches. It
will be possible to investigate the intracellular Ca2+
concentration ([Ca2+]i)
in glomerula with an intact Bowman capsule and to shorten the time period between isolation of the glomerulum and an experiment by using confocal laser scanning microscopy. In addition, it might be
possible to identify a [Ca2+]i
reponse not only in podocytes but also in other glomerular cell types.
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RT-PCR of single podocytes.
To study the expression of genes in single podocytes, Schröppel
et al. (51) have recently established a technique that allows the
identification of specific mRNA species from single aspirated podocytes
(Fig. 2). After a short-time treatment of a
glomerulum with neuraminidase, a single podocyte was aspirated into a
micropipette and harvested. By a freeze-thaw cycle, the cytoplasmatic
membrane was ruptured and RT of RNA could be performed. Thereafter,
cDNA was amplified with sequence-specific oligonucleotide primers
including intronic sequence primers. Several sets of control experiments were performed to exclude the amplification of nonpodocyte cDNA. By using this method, mRNA of podocyte-specific markers, namely,
glomerular epithelial protein 1 (GLEPP-1), Wilm's tumor protein 1 (WT-1), and vascular endothelial growth factor (VEGF), which is known
to induce proliferation of endothelial cells and to increase vascular
permeability (40), could be amplified in 28-67% of the harvested
podocytes (51). In contrast, von Willebrand factor, a marker for
endothelial cells, could not be detected (51). The single-cell RT-PCR
of podocytes will advance our understanding of the roles of genes in
podocytes, more so if it is possible to semiquantify the amount of cDNA
obtained and to isolate podocytes from glomerula of patients with
specific glomerular diseases.
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Cell culture of podocytes. In the past it was assumed that cultured proliferating glomerular epithelial cells with a cobblestone appearance were podocytes (4, 13). In contrast to the cultured cells, the podocyte in vivo may not proliferate and has an octupus-like shape (35). In addition, the pattern of several antigens on cultured glomerular epithelial cells did not fit well to the antigen pattern of podocytes in vivo. Thus it was suggested that glomerular epithelial cells in culture are not podocytes but in fact are glomerular parietal epithelial cells (25). Recently, the culture and characterization of differentiated podocytes was accomplished successfully (41). The differentiated podocytes have foot processes and develop from undifferentiated podocytes with a cobblestone appearance. Both the differentiated and undifferentiated phenotype stained positively with an antibody against WT-1, a podocyte-specific nuclear protein, whereas only the differentiated podocyte stained positively with an antibody against synaptopodin, a protein that is located in podocyte foot processes in vivo (41). Therefore, it is possible to identify podocytes by using podocyte-specific antibodies and to distinguish between undifferentiated and differentiated podocytes. Differentiated podocytes in primary culture exhibit very little proliferative activity, and thus it is difficult to perform experiments that require a large number of cells. Therefore, a conditionally immortalized podocyte cell line has been derived from a transgenic mouse expressing a temperature-sensitive SV 40 large T antigen (42). Cells that are grown under nonpermissive conditions, i.e., at 37°C, stop growing and exhibit many morphological and immunologic properties of differentiated podocytes (42). Thus there is no doubt that podocytes can be propagated in cell culture, and it is easier, in comparison to the investigation of the podocytes in situ, to investigate physiological and molecular properties of podocytes in vitro. However, although cultured differentiated podocytes possess many in vivo properties of podocytes, biological functions of the cells may change during culture, and therefore results obtained from these cells have to be interpreted with care.
Cellular Signaling and Hormones in Podocytes
Vasoactive hormones activate a
Ca2+-dependent
Cl
conductance in podocytes.
Vasoactive hormones like ANG II are known to regulate the glomerular
filtration rate via modulation of the tone of the glomerular arterioles
and a decrease in the ultrafiltration coefficient
Kf. ANG II increases the urinary protein excretion
rate and induces a loss of glomerular size-selective functions (27).
ANG II also acts as a growth hormone. It stimulates proliferation of
glomerular endothelial and mesangial cells and the synthesis of
extracellular matrix proteins like collagen IV (27). The effects of ANG
II are critical for the development of glomerulosclerosis. It has been
shown that a reduction of ANG II levels by
angiotensin-converting-enzyme (ACE) inhibitors slows the progression of
glomerulosclerosis in experimental and human glomerular diseases (38).
Within the glomerulum ANG II was thought to act preferentially on
mesangial cells (5). However, it has been shown that ACE inhibitors
ameliorate glomerular function, and in contrast to other
antihypertensive agents, reduce podocyte hypertrophy in rat kidneys
after subtotal nephrectomy, indicating that podocyte morphology may be
directly influenced by ANG II (2). We have recently shown that ANG II depolarized podozytes in the intact rat glomerulum. A 1 nM threshold concentration of ANG II was required to induce a depolarizaion of
podocytes. A half-maximal response was observed at 10 nM ANG II. (20).
concentration, indicating that ANG
II activates a Cl conductance in podocytes (20).
In the presence of losartan the ANG II-mediated depolarization was
completely and reversibly inhibited, indicating that podocytes possess
ANG II type 1 (AT1) receptors (20). The
influence of ANG II on the function of podocytes could have been
mediated indirectly through an endothelial or mesangial cell-released
cytokine or hormone. This is rendered highly unlikely because ANG II
also depolarized differentiated rat podocytes in culture via an
AT1 receptor (20). Activation of the AT1
receptor is known to increase [Ca2+]i in several cell types (27).
To investigate a possible influence of ANG II on
[Ca2+]i and to study the mechanisms
involved, fluorescence measurements with the Ca2+-sensitive
dye fura 2 were performed in cultured rat podocytes (24). ANG II
concentration dependently increased
[Ca2+]i in rat podocytes with an
ED50 of 3 nM. The ANG II-induced
[Ca2+]i increase was mediated by an
AT1 receptor and was due to both a release of
Ca2+ from intracellular stores and an influx of
Ca2+ from the extracellular space (24). An L-type
Ca2+ channel antagonist did not inhibit the
Ca2+ influx induced by ANG II, indicating that the influx
did not occur via L-type Ca2+ channels. In addition, the
absence of a Ca2+ increase in the presence of a solution
with high extracellular K+ concentration suggests that
podocytes do not possess L-type Ca2+ channels. The
Ca2+ influx might be due to an opening of a nonselective
ion channel as flufenamate, a blocker of nonselective ion channels,
inhibited the Ca2+ response to ANG II (24).
Meanwhile, the presence of AT1 and AT2
receptors was also demonstrated in undifferentiated rat podocytes in
long-term culture (52). Surprisingly, ANG II increased cAMP in these
podocytes. High (0.1 µM) and low concentrations (10 pM) of ANG II
were nearly equipotent in increasing cAMP (52). ANG II-mediated cAMP
increase could only partially be inhibited by either high
concentrations of losartan or PD-123,319, an AT2 receptor
antagonist. Only the simultaneous addition of both antagonists
completely inhibited the effect of ANG II on cAMP increase in
podocytes, suggesting that it was mediated by both ANG II receptors
(52). Further studies have to clarify whether there is a possible
interaction beween ANG II-mediated cAMP and Ca2+ signaling
in podocytes and whether ANG II-mediated cellular signaling differs in
undifferentiated and differentiated podocytes.
Several other agonists have been reported to modulate
[Ca2+]i in podocytes like ANG II
(3, 7, 8, 23, 26, 42, 47, 48, 50, 54-56). Table.
1 summarizes the respective hormones with
their receptors and signaling pathways in undifferentiated and
differentiated podocytes. In addition, it has been reported that the
damage of podocytes mediated by complement C5b-9 complex is associated
with an [Ca2+]i increase and an
activation of phospholipase C (16). The activation of
[Ca2+]i and phospholipase resulted
in an inhibition of complement C5b-9 complex-mediated podocyte injury
(15).
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2-adrenoceptors,
respectively, leading to the opening of a cAMP-dependent
Cl conductance (7, 8, 26). A parathyroid hormone
(PTH)-stimulated cAMP increase has been detected in rat podocytes (17).
The presence of a PTH/PTH-related peptide (PTHrP) receptor mRNA was
confirmed by in situ hybridization, and a unique PTH/PTHrP receptor
transcript was detected in Northern blot studies in cultured human
podocytes (37).
Rat podocytes in vivo possess -atrial natriuretic peptide (ANP)
receptors (33) and an increase of cGMP concentrations in human
podocytes is induced by ANP (4, 10). Infusion of ANP in adult or
neonatal rats increases the cGMP level in podocytes, with a higher
threshold for activation in immature animals, suggesting that the
regulation of cGMP may play a role in podocyte development (11).
What is the biological significance for hormone-mediated changes in
pododcyte function?
1) Hormone-induced cellular signaling might modify the
contractile structures of podocyte foot processes, resulting in an alteration of Kf. Direct evidence for this
hypothesis is still missing. It is proposed that an increase in
[Ca2+]i or cAMP induces a narrowing
of the filtration slits, leading to a decrease in
Kf, whereas an increase in cGMP might have an opposite effect on Kf (53).
2) Vasoactive hormones may also alter charge properties of the
podocyte and thereby enhance urinary protein excretion (46).
3) Norepinephrine and ANG II are thought to contribute to the
pathogenesis of acute renal failure (14, 49). For example, infusion of
norepinephrine into the renal artery induced acute renal failure and
damage to the filtration barrier, with severe changes in podocyte
morphology (14). Acute renal failure induced by norepinephrine may
therefore, at least in part, be due to direct norepinephrine-mediated
injury of podocytes.
4) In several experimental models of chronic renal failure,
podocyte damage initiates and maintains the progression of
glomerulosclerosis (34). An understanding of the cellular mechanisms of
the pathogenesis of glomerulosclerosis is unclear, but the activation
of podocyte signaling systems by ANG II and other vasoactive hormones
probably contributes to podocyte injury in chronic renal failure (2). It will therefore be important to specify which of the multiple intracellular signaling cascades activated by ANG II is responsible for
podocyte injury and whether these signaling cascades are also activated
by other hormones or cytokines.
NAD(P)H oxidase activity is stimulated by the vasoactive agent ATP in podocytes. Reactive oxygen species (ROS) are important mediators in Heyman nephritis, a model for human membranous nephropathy, characterized by subepithelial immune complex deposition and proteinuria. In Heyman nephritis a complement-mediated expression of cytochrome-b558, a major component of the NADPH oxidoreductase complex, which forms superoxide, has been detected in podocytes in vivo. ROS are produced locally and reach the glomerular basement membrane matrix, where lipid peroxidation adducts are formed. This oxidative modification probably leads to a dimerization of type IV collagen molecules of the glomerular basement membrane and proteinuria (for review, see Ref. 31). Recently, we have shown that cultured human podocytes can produce superoxide and that extracellular ATP time and concentration dependently increase the production of superoxide in podocytes (22). Both NADH and NADPH oxidases were activated by ATP, whereas the activity of xanthine oxidases was unchanged, indicating that NAD(P)H-dependent oxidases represent the major source for superoxide in podocytes. RT-PCR studies showed that podocytes express mRNA for the NADPH oxidase subunits p22phox, gp91phox (both subunits form the cytochrome b-58 complex), p47phox, and p67phox (22). p67phox was transiently increased by ATP. Actinomycin D, an inhibitor of transcription, and cycloheximide, an inhibitor of RNA translation, inhibited the ATP-induced activation of NAD(P)H oxidase, indicating that ATP modulates enzyme activity at transcriptional and translational levels (22). The activation of superoxide production by ATP and in all likelihood by other vasoactive hormones may play an important role in homone-induced injury of podocytes. Future studies will have to clarify the different cellular roles for the NAD(P)H oxidase system in podocytes. Also, they will have to investigate whether an inhibition of single subunits of the NADPH oxidase complex reduces podocyte injury.
New Genes in Podocytes
Recently, several new genes, megalin, nephrin, podoplanin, GLEPP-1, and synaptopodin, have been identified in podocytes.Megalin. Megalin is a 600-kDa transmembrane protein belonging to the LDL receptor gene family and was identified in rat podocytes as the target of immune deposit-forming antibodies in Heyman nephritis (21, 31). Megalin is an endocytotic receptor that has been shown to contribute to the the uptake of lipoproteins in rat podocytes (30). In addition, within the kidney, it serves as a receptor for the reabsorption of several distinct molecules in proximal convoluted tubule (12).
Nephrin. Congenital nephrotic syndrome of the Finnish type is an autosomal recessive disorder characterized by proteinuria in utero and nephrosis at birth. Recently, nephrin, the major gene affected in congenital nephrotic syndrome of the Finish type, has been identified by positional cloning (32). Nephrin is a 135-kDa putative transmembrane protein of the immunoglobulin superfamily of cell-adhesion molecules, which is specifically expressed in podocytes (32). The physiological role of nephrin is unclear, but it is assumed to be an adhesion receptor and a signaling protein that may play a crucial part in maintaining the integrity of podocyte foot processes (32).
Podoplanin. Recently, podoplanin, a 43-kDa integral membrane glucoprotein localized on the surface of rat podocytes, has been cloned (9). Glucoproteins with similar sequences as podoplanin were also found in other cells, like lung epithelial cells and osteoblasts (9). Podoplanin is transcriptionally downregulated in puromycin nephropathy, an experimental model for minimal change disease (9). After injection of polyclonal rabbit anti-podoplanin IgG into rats, IgG selectively binds to podocytes at a common binding site (39). Some IgGs induced a retraction of podocyte foot processes that was accompanied by transient proteinuria. Podoplanin therefore seems to play a crucial part in the maintenance of podocyte foot processes, and hence, glomerular permeability (39).
GLEPP-1. GLEPP-1 is a 132-kDa membrane protein-tyrosine phosphatase with a large extracellular domain containing eight fibronectin type III-like repeats, a hydophobic transmembrane segment, and a single protein-tyrosine phosphatase domain (57). GLEPP-1 was demonstrated in podocyte foot processes, and it might also be present in the brain. GLEPP-1 has been assumed to contribute to the control of podocyte foot processs structure by regulating tyrosine phosphorylation of proteins in podocytes (57). Reduction of GLEPP-1 protein has been demonstrated in a rabbit anti-glomerular basement membrane model of glomerular injury, and focal-to-diffuse disappearance of GLEPP-1 protein has been detected in human kidney biopsies with crescentic nephritis (58).
Synaptopodin. Synaptopodin, a novel, actin-associated protein, has been recently cloned (40). The protein sequence codes for a 685-aa polypeptide with a molecular mass of 73.7 kDa (40). Synaptopodin is expressed in podocyte foot processes and in the telencephalon. Synaptopodin is exclusively expressed in mature podocytes and has therefore been regarded as a maturity marker. Its function is not understood, but it is assumed to play a role in the motility of podocyte foot processes (40). Synaptopodin expression is preserved in human glomerulopathies that are associated with reversible foot process fusion. On the other hand, it disappears in areas of capillary wall necrosis, cellular crescents, or early and advanced stages of focal segmental sclerosis (FSGS), even in the presence of podocytes (28). In collapsing idiopathic glomerulosclerosis, a severe form of FSGS with a poor prognosis, the change of podocyte morphology is associated with a reduced expression of the maturity markers synaptopodin, WT-1, GLEPP-1, podocalyxin, common acute lymphoblastic leukemia antigen, and the C3b receptor, and an increased expression of the proliferation marker Ki-67 (6). The same alterations of the expression patterns of the markers have been observed in HIV-associated nephropathy, whereas their expression was not altered in minimal change and membranous nephropathy (6). Therefore, the loss of synaptopodin and other specific markers of the podocyte may be associated with shape changes in collapsing FSGS.
Outlook
The recent advances in physiological, molecular biological, and cell culture techniques will provide an understanding of the precise role of vasoactive hormones and the function of newly discovered genes in the podocyte. The identification of the signaling pathways leading to changes in podocyte cell shape and retraction of its foot processes will advance the understanding on the pathomechanisms of proteinuria. They also might lead to new strategies in the therapy of glomerular diseases.| |
ACKNOWLEDGEMENTS |
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I regret that not all pertinent articles could be cited in this brief review due to a lack of space. The contributions of the following past and present members of the laboratory remain the basis for many of the findings summarized herein: Joachim Gloy, Karl-Georg Fischer, Stefan Greiber, Roland Nitschke, Anna Henger, Martin Bek, Tobias Huber, and Pascal Kowark. I would like to thank Rainer Greger for his helpful comments.
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FOOTNOTES |
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The work was supported by grants from the Deutschen Forschungsgemeinschaft (Pa-483).
Address for reprint requests and other correspondence: H. Pavenstädt, Medizinische Universitätsklinik, Abt. Nephrologie, Hugstetterstr. 55, D-79106 Freiburg, Germany (E-mail: paven{at}mm41.UKL.unifreiburg.de).
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