Modulation of Podocyte Phenotype and the Emerging Role of Biomarkers in Podocytopathies
New York University
New York, NY
The unraveling of the unique molecular apparatus of the podocyte has increased tremendously in the
last few years. Knowledge about podocyte biology and molecular anatomy has improved our understanding of
pathomechanisms of nephrotic syndrome, the diagnosis, and classification of diseases that we can call
Podocytes are post-mitotic cells whose function depends on
their cytoarchitecture. They are composed of a cell body, primary processes and foot processes
(connected to the cell body by the primary processes). The podocyte surface is divided by the slit
diaphragm (SD) in the luminal surface, facing the urinary space, and abluminal surface, facing the
glomerular basement membranes (GBM). Podocytes serve several functions including:
- Regulation of permselectivity through cell-cell interaction at the level of SD
- Structural support for the glomerular capillaries though a network of interdigitating processes
- Counteraction the intracapillary hydrostatic pressure
- Remodeling the GBM
The term refers to a group of glomerular diseases
characterized by proteinuria or nephrotic syndrome, clinically, and podocyte damage, morphologically.
The spectrum of diseases that fall under the umbrella of podocytopathies ranges from congenital nephrotic
syndrome (CNS), minimal change disease (MCD), to focal segmental glomerulosclerosis (FSGS), and
collapsing glomerulopathy (CGP).
Whether proteinuria is selective or non-selective, this clinical feature is
results from podocyte damage. A common feature in all forms of podocytopathies is foot process
effacement. Foot process effacement may be, partial /focal if it involves less than 50-75% of the
capillary surface, or extensive /diffuse, when it involves most the capillary surface.
Podocytes are injured in many forms of experimental and human glomerular
disease. Independent from the underlying disease, the early events of podocyte injury are characterized
by alterations of the slit diaphragm and foot process effacement.
Based on recent progress in the molecular pathology of podocytes, several causes of foot process effacement (and proteinuria) can be identified:
- Impaired formation of the slit diaphragm complex and its associated lipid rafts
- Abnormalities of the adhesive interaction between podocytes and GBM
- Alterations of transcription factors
- Abnormalities of the actin-based cytoskeleton
- Alterations of the apical domain of podocytes
- Mechanical stress
- Viral infection
- Acute ischemic injury
- Toxic/metabolic effect
Molecular Anatomy of the Podocyte Foot Process Cytoskeleton
The podocyte foot processes contain a contractile system composed of actin, myosin-II, α-actinin-4,
talin, vinculin and synapotopodin that is connected to the GBM via integrin. The linkage of the actin
cytoskeleton to the slit diaphragm components (nephrin, and P-cadherin) may be mediated by CD2AP, or by a
complex of Z0-1 or beta and gamma-catenin. The actin cytoskeleton is well suited to integrate different
signaling pathways from the matrix. Disruption of any of these pathways may lead to reorganization of
the actin cytoskeleton and foot process effacement as seen with nephrotic syndrome. [N, nephrin; P-Cad,
P-cadherin, α, α-catenin β-catenin, γ-catenin Z, Z0-1, α3, α3-integrin; β1, β1-integrin; V, vinculin; T,
talin; P, paxillin; α-act 4,α-actinin-4; synpo, synaptopodin; GBM, glomerular basement membranes.]
SD is composed of a complex of proteins located in the
extracellular space, bridging adjacent foot processes. It is composed of different proteins including:
mFAT1, nephrin, the nephrin homologue Neph1, CD2AP, and podocin. The recent discovery of these proteins
as part of the SD has emphasized the critical role of the SD in maintaining the normal function of the
filtration barrier. The identification of the nephrin gene NPHS1 elucidated the genetic defect
underlying congenital nephrotic syndrome of Finnish type. Patients lacking normal nephrin have severe
proteinuria and foot process effacement at birth and rapidly develop glomerular sclerosis and ESRD. The
podocyte phenotype lacks staining for nephrin on IF or immunohistochemistry and ultrastructurally shows
extensive foot process effacement. The role of nephrin in maintaining the function of the filtration
barrier is also demonstrated experimentally by injection of anti-nephrin Ab into animals, which resulted
in proteinuria. Similarly, inactivation of NHSP1 in mice results in foot process effacement and
proteinuria. Both in animal models and in humannephrotic syndrome, when foot process effacement occurs,
nephrin is found redistributed in the apical (luminal) portion of the podocyte plasma membrane. Another
report shows that the expression of nephrin is lower in areas of foot process effacement versus those
areas where the foot processes are preserved. The question is whether immunostaining for nephrin may
help to discriminate between the different forms of FSGS, MCD or CGP. Based on the available literature,
the use of specific antibodies to nephrin is limited to cases of congenital nephrotic syndrome.
Mutations of NPHS2, which encodes for another protein located at the SD, podocin, are the genetic
cause of autosomal recessive, steroid-resistant nephrotic syndrome in pediatric and adult populations.
Podocin is localized at the insertion of the SD and interacts with both nephrin and CD2AP. It appears
that podocin serves in the structural organization of the SD, acting as a scaffolding protein, hence the
decrease in expression and/or distribution may influence both the cytoskeleton and the SD. Mice lacking
podocin develop congenital nephrosis. Mutations in both podocin gene alleles lead to a wide range of
human diseases from childhood onset steroid resistant FSGS and minimal change disease, to adult FSGS. A
single report shows that children with steroid resistant and steroid sensitive nephrotic syndrome and a
variety of diseases from minimal change disease, to mesangial proliferation and IgA nephropathy, have
reduced expression of podocin. Moreover, this study shows a non-specific correlation between podocin
expression and response to steroid therapy.
One of the most exiting recent discoveries has been made by the group of Andrew Shaw. Mice lacking
CD2AP rapidly develop podocyte injury followed by mesangial sclerosis, indicating that indeed, podocytes
are the primary cause of glomerular damage. So far only 2 patients with FSGS have been shown to have
mutations in the gene encoding for CD2AP (unpublished data).
MFAT1 is a protein also localized in the SD and mice lacking mFAT1 exhibit perinatal mortality. So
far, no human form of proteinuria has been related to mFAT1. ZO-1 is a protein localized at the
insertion of the SD, but there is no described disease of the foot processes associated with a defect of
Abnormalities of the Adhesive Interaction Between Podocytes and GBM
Several factors contribute to maintain the highly ordered foot process architecture. Some of these
proteins are localized in the SD, others are part of the actin-based cytoskeleton, and others are located
at the abluminal side (sole) of podocytes. α3-β1 integrin and α- and β dystroglycan
are the major proteins responsible for the adhesion of podocytes to the underlying GBM. Interesting, the
integrin-binding status may influence the cytoskeleton organization and thereby contribute to determining
the foot process shape. Indeed, blockage of the β1-integrin binding site by specific antibodies
leads to foot process effacement, proteinuria and detachment. Also the dystroglycans, heterodimeric
proteins composed of a transmembrane component (β) and an extracellular subunit (α), are
connected to the actin-based cytoskeleton through urotrophin (the podocyte equivalent of dystrophin in
skeletal muscle). One of the most exciting studies from a practical point of view has demonstrated that
in MCD, during the proteinuric state, the expression of dystroglycan and β1-integrin is markedly
reduced, whereas dystroglycan is preserved in FSGS, despite a comparable amount of proteinuria. The
expression of dystroglycan and β1-integrin returns to normal once the foot processes are restored.
This result is unexpected given the fact that on ultrastructural analysis, detachment of podocytes from
the GBM is never observed in MCD, whereas it is a relatively common feature in FSGS. Several conclusions
can be made: first, this is a phenomenon specific to steroid sensitive MCD, and may explain how proteins
leak into the urinary space in the absence of visible podocyte detachment. Second, MCD and FSGS have in
common foot process effacement but are two distinct diseases and some additional pathomechanisms must be
responsible for podocyte detachment in FSGS. The relationship between MCD and FSGS has been
controversial. Some cases with a diagnosis of steroid resistant MCD at the first biopsy have a diagnosis
of FSGS at the second biopsy, raising the question whether these cases are FSGS, where the segmental
lesion has not been sampled. Or do these specific cases represent a form of MCD that progresses to FSGS?
The use of markers such as dystroglycan may help discriminate true MCD, from early FSGS.
Alterations of Transcription Factors
Three major transcription factors
appear important in podocytopathies: Wilm's tumor 1 (WT-1), PAX2, and LMX1B. WT-1 is selectively
expressed in mature podocytes, whereas WT-1 is expressed in all cells during development. PAX2 gene
encodes a transcription factor expressed early during development and is a WT-1 target gene. Therefore,
when glomeruli mature and WT-1 expression increases and is restricted to podocyte only, PAX2 expression
decreases. Both these factors are very important for metanephric development. WT-1 expression is
altered in congenital and acquired glomerular diseases. Among the congenital disorders Denys-Drash
syndrome and Fresier syndrome should be mentioned. Denys-Drash syndrome is characterized by early onset
of nephrotic syndrome, male pseudohermaphroditism, and neuroblastoma. The glomerular lesions are diffuse
mesangial sclerosis, accompanied by podocyte hypertrophy and proliferation. Podocyte phenotype is
characterized by loss of expression of WT-1 by immunostaining with increased expression of PAX2 and
proliferative markers such as Ki67. Interestingly, in collapsing glomerulopathy, which is not
characterized by mesangial sclerosis but by collapse of the glomerular capillaries and podocyte
proliferation with pseudocrescents formation, WT-1 expression is decreased in collapsed and non-collapsed
glomeruli. PAX2 and Ki67 expression are up-regulated, indicative of podocyte de-differentiation and
re-entry into the cell cycle.
Nail patella syndrome is an autosomal dominant disease characterized by proteinuria, skeletal
abnormalities, and nail hypoplasia, and is due to defect in LMX1B. LMX1B regulates the expression of
several podocyte genes critical for podocyte differentiation and function. The real mechanism of this
disease is still unclear. LMX1B-/- podocytes have reduced number of foot processes, are dysplastic, and
lack typical SD. These unique findings indicate an arrest in development, however, they have normal
levels of nephrin, synaptopodin, ZO-1, and α-3 integrin.
Abnormalities of the Actin-based Cytoskeleton
cytoskeleton of foot processes contains numerous proteins and the most important in this context are
α-actinin-4 and synaptopodin. There are 3 different recognized podocyte phenotypes in regard to
cytoskeleton reorganization or expression. It is well known that in nephrotic syndrome, and this is
particularly evident in MCD but also in FSGS, reorganization of the actin-based cytoskeleton occurs, and
intermediate filaments are observed condensed against the "sole" of podocytes, rather than sparsely
distributed in the cytosol. In these conditions, no significant alteration of the cytoskeletal protein
expression has been described. On the contrary, in certain forms of autosomal dominant FSGS, mutations
of the gene encoding for α-actinin-4 have been found. This disease is highly but not fully
penetrant, leading to proteinuria and renal insufficiency in adulthood. The mutant actinin shows higher
affinity for F-actin. α-actinin-4 deficient mice are different from mouse models deficient in
nephrin, WT-1, or podocin, and do not have nephrosis at birth but develop it later in life later in life,
as in human disease. This indicates that alterations in α-actinin-4 lead to podocyte damage and
FSGS by causing subtle cytoskeletal changes. Of note, mice lacking synaptopodin, another component of
the cytoskeleton, do not have any specific phenotype and foot process effacement and sclerosis occurs
only after partial nephrectomy. These data indicate that there is probably a compensatory mechanism
within the cytoskeleton if any of the components are missing, but podocytes are more prone to injury.
The question is whether α-actinin-4 staining can be used as a useful marker to identify this form of
autosomal dominant FSGS or potential sporadic forms in adults. Although this aspect needs to be further
investigated, immunostaining does not appear to be particularly useful. Quantification of
intraglomerular mRNA, after laser capture microdissection has shown positive correlation forthe
expression levels of ACTN4, GLEPP-1, synaptopodin, dystroglycan,WT-1, and nephrin in acquired proteinuric
diseases, but the expression of a single protein was not predictive of disease.
The other important component of the cytoskeleton is synaptopodin. Synaptopodin expression has been
shown to be markedly reduced in CGP, whereas it is generally well preserved in MCD and FSGS. In
particular, synaptopodin expression is not only reduced in the collapsed glomeruli, but also in the
non-collapsed ones, indicating that in certain forms of CGP, the podocyte injury precedes the glomerular
Alterations of the Apical Domain of Podocytes
On the luminal side,
podocytes are equipped with a well-developed glycocalyx, having a negative charge, mostly composed of
podocalyxin. Podocalyxin is expressed in both podocytes and endothelial cells early during development.
Podocalyxin is of critical importance for the formation and preservation of cell architecture.
Podocalyxin knock out mice have flattened podocytes. GLEPP-1, a transmembrane protein tyrosine phosphate
inserted in the luminal surface of podocytes, may also have an important role in regulating structure and
function of podocytes. In human diseases, it has been demonstrated that the expression of both
podocalyxin and GLEPP-1 is markedly reduced in FSGS, in areas of sclerosis, which is expected since no
podocytes should be present in those areas, and in areas of podocyte hypertrophy and hyperplasia
(pseudocrescents) in CGP. Of note, podocalyxin expression is well preserved in endothelial cells,
indicating that indeed CGP is a podocyte disease.
FSGS can be idiopathic, secondary to genetic defects
affecting proteins that are part of the cytoskeleton or the SD, or secondary to mechanical stress. The
latter mechanism is involved in those forms of FSGS due to hyperfiltration (single kidney, obesity,
hypertension, and others). There is in vivo and in vitro evidence of the role of podocyte stretching in
the development of "secondary" FSGS. First, lessons from the animal models teach us that FSGS develops
after significant ablation of renal parenchyma. It has been suggested that segmental sclerosis is
preceded by increased in glomerular area (glomerulomegaly), and accompanied by mechanical stretching of
podocytes. Podocytes are post-mitotic cells and, with the only exception of collapsing glomerulopathy
and Denys-Drash syndrome, they cannot proliferate. Therefore, under mechanical stress, podocytes react
by undergoing hypertrophy to maintain their function as the filtration barrier and attempt to cover a
larger surface of GBM, by reorganization of the actin-based cytoskeleton. This leads to foot process
effacement, focal detachment with pseudocyst formation, to complete detachment and death (podocyturia),
and GBM are left "denuded". This step is a point of non-return to synechia formation (adhesion of the
GBM to the Bowman capsule). It has been suggested that parietal cells migrate from the Bowman capsule to
cover the naked GBM. In vitro, this phenomenon has been confirmed and has been shown that, once
podocytes are mechanically stretched, they undergo reorganization of the actin-based cytoskeleton but not
alteration of expression of podocyte proteins. The change in phenotype is restricted to morphologic
variation in size and shape but not protein expression. Moreover, mechanically stretched podocytes
re-enter the cell cycle, do not proliferate but undergo hypertrophy. In human disease, it has been
demonstrated that glomerulomegaly occurs in secondary forms of FSGS, e.g. hypertension- or
obesity-mediated. In these forms no change in podocyte phenotype has been described except for focal
foot process effacement.
Viral infection has been considered the cause of some
forms of CGP. Patients with collapsing glomerulopathy should be tested for HIV, parvovirus B19, SV40 and
CMV (one case only in the literature). Both HIV and parvovirus B19 mRNA have been demonstrated in
podocytes and epithelial cells in biopsies form patients with CGP. The podocyte phenotype in these
diseases is not only de-differentiated, but also trans-differentiated and dysregulated. Podocytes lose
their foot processes along with primary processes and assume a cuboidal shape, which resembles immature
podocytes. Moreover, the expression of specific podocyte maturity markers, podocalyxin, GLEPP-1, CALLA,
is down-regulated (de-differentiation). De-differentiation is accompanied by re-entry of the cell cycle
and proliferation, which is reflected by the positive staining for Ki-67 in areas of pseudocrescent
formation. Podocytes acquire properties of other cell lines and express CK and CD68
(trans-differentiation), and simultaneously lose molecules, which are expresses at any developmental
stage, such as WT-1 (dysregulation), with consequent up-regulation of PAX2. This phenomenon has also
been confirmed in animal models of HIV-1 infection, where podocyte damage, reflected by the up-regulation
of desmin expression, occurs early during the disease, when the HIV-1 mRNA can be demonstrated in
podocytes. This is accompanied by attenuation of synaptopodin expression, and followed by sclerosis,
pseudocrescents formation, complete loss of synaptopodin and WT-1, and Ki-67 expression. In the HIV
model of CGP, two major fragment of the HIV genome have been implicated in the pathogenesis of the renal
disease: Nef and Vpr. We recently created a model of glomerular collapse/sclerosis where Vpr expression
is driven by podocin as promoter. Once Vpr is activated, mice develop proteinuria, podocyte hypertrophy
and hyperplasia, and later glomerulosclerosis.
Acute Ischemic Injury
CGP was initially described in association with HIV
infection and called HIV-associated nephropathy (HIV-AN) or as an idiopathic form. More recently new
form of CGP have been described in addition to the virus-associated ones, and they appear to be due to a
reactive process to acute ischemia rather than a primary podocyte injury. Frequently pathologists
encounter cases with glomerular collapse and pseudocrescents formation in transplant biopsies. Whereas
some of these cases may represent a recurrent disease, in other cases no history of collapsing
glomerulopathy prior to the transplant is present. In many of these biopsies, thrombotic microangiopathy
(TMA) can be demonstrated. The pathomechanism involved in these forms is still unknown, and podocyte
changes may be considered reactive to ischemia. It is interesting to speculate that VEGF-mediated cross
talking between podocytes and endothelial cells may occur and play a role in the pathomechanism. The
question is whether we have any biomarker to discriminate between the reactive and primary form of
podocyte injury and collapse. Synaptopodin and WT-1 may be useful markers. Whereas in viral-associated
CGP, the loss of synaptopodin is global and diffuse not only in the affected glomeruli, but also in the
non-affected ones, preliminary studies show that in reactive forms of collapsing glomerulopathy, loss of
synaptopodin is restricted to the affected glomeruli.
Recently, CGP has been associated with a variety
of diseases (myeloma, Still's disease, tuberculosis, and others) or use of medications such as
pamidronate or interferon. Medications also cause podocyte injury without proliferation and collapse,
and those include pamidronate, interferon and NSAID. The pathogenetic mechanism underlying these
subgroups of CGP is different: in pamidronate-associated disease it has been suggested that the toxic
effect of pamidronate is mediated by GTPase, impairment of cell energy via ATPase, and disruption of the
cytoskeleton. In CGP associated with myeloma, Still's disease or tuberculosis it is possible that the
process is mediated by inflammatory mediators (interferon?). Moreover, interferon-induced CGP has also
been reported. It has to be mentioned that in all these reports viral infection has not been excluded,
and although most of the patients are HIV negative, none of them have been tested for parvovirus B19.
Moreover, pamidronate-associated podocyte injury has been described also in few cases of MCD. Studies are
still in progress to better characterize the podocyte phenotype in these patients. We recently presented
a limited study including patients with idiopathic, TMA-associated and pamidronate-associated collapsing
glomerulopathy. Cases were stratified based on the presence or absence of synaptopodin expression in the
non-affected glomeruli. We found that, whereas the pamidronate-associated cases behave as "reactive"
CGP, and synaptopodin expression was preserved in non-collapsed glomeruli, among the cases with proven or
suspected TMA and idiopathic forms, the podocyte phenotype varied from diffusely de-differentiated and
dysregulated to "reactive pattern". Studied with antibodies against parvovirus B19 need to be done to
exclude a virus-mediated process in those cases that present with dysregulated phenotype.
Considering this new knowledge on podocyte phenotype, the next logical step would be to try to
re-classify well-known morphologic entities, previously identified based on histologic features.
Although the morphology remains the guide to identify the major subgroups of podocytopathies (MCD, FSGS
and CGP), additional information, including podocyte phenotype and detailed clinical history, may be
helpful to sub-classify these entities, learn more about prognosis and better target the therapy in each
Proposed Scheme for Work Up of Renal Biopsies with Podocytopathies
- Steroid sensitive MCD = 100% foot process effacement + dystroglycan staining
- Steroid resistant MCD = 100% foot process effacement + dystroglycan staining (positive?), + nephrin staining (if CNS is suspected), + podocin staining (variable)
- Congenital nephrotic syndrome = 100% foot process effacement + nephrin staining
- Mesangial sclerosis =WT-1, PAX2 and Ki-67
- Idiopathic FSGS = Extensive foot process effacement +? synaptopodin, podocin staining
- Familial FSGS = variable degree of foot process effacement + podocin, nephrin, α-actinin-4.
- Secondary FSGS = glomerulomegaly + <50% foot process effacement +clinical history of HTN or obesity.
- Collapsing glomerulopathy = collapse and pseudocrescents + Hx of viral infection and/or staining for parvovirus B19 + synaptopodin + WT-1 + PAX2, + Ki-67
Classification of Podocytopathies
|Histology ||Pathologic variant ||Pathogenetic factor|
|Normal ||Acquired MCD ||?Dystroglycan|
|Drug induced ||NSAID, pamidronate, interferon|
|Genetic defect ||Nephrin, podocin, ?19q13|
|Mesangial sclerosis ||DDS & FS ||WT 1|
|Sporadic forms MS ||WT 1|
|Focal segmental glomerulosclerosis ||Idiopathic ||Unknown|
|Permeability factor ||Unknown|
|Genetic defect ||Podocin,α-actinin-4, TRPC6, LMX1B, ?19q13 , CD2AP|
|Hyperfiltration-associated ||Mechanical stress|
|Collapsing glomerulopathy ||Idiopathic ||Unknown|
|Virus-associated ||HIV; parvovirus B19; SV40; CMV|
|Infectious diseases ||leishmaniasis; filariasis; TB|
|Secondary to ischemia ||TMA; severe vasculopathy|
|Drug-induced ||Pamidronate, interferon|
|Autoimmune disease ||?|
|Genetic defect ||?|
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