Barbara Lewko

Gavin Iain Welsh

Maciej Jankowski

Frontiers in Endocrinology

PubMed

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Editorial: Podocyte Pathology and Nephropathy

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EDITORIAL
published: 17 September 2015
doi: 10.3389/fendo.2015.00145
Edited by:
Aaron Vinik,
Eastern Virginia Medical School, USA
Reviewed by:
Ramin Tolouian,
Eastern Virginia Medical School, USA
*Correspondence:
Barbara Lewko
blew@gumed.edu.pl
Specialty section:
This article was submitted to
Diabetes, a section of the journal
Frontiers in Endocrinology
Received: 23 June 2015
Accepted: 02 September 2015
Published: 17 September 2015
Citation:
Lewko B, Welsh GI and Jankowski M
(2015) Editorial: Podocyte pathology
and nephropathy.
Front. Endocrinol. 6:145.
doi: 10.3389/fendo.2015.00145
Editorial: Podocyte pathology and
nephropathy
Barbara Lewko1,2*, Gavin Iain Welsh3 and Maciej Jankowski2,4
1 Department of Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland, 2 Laboratory of
Molecular and Cellular Nephrology Gdansk, Miroslaw Mossakowski Medical Research Center of the Polish Academy of
Sciences, Warsaw, Poland, 3 Academic Renal Unit, University of Bristol, Bristol, UK, 4 Department of Clinical Chemistry, Medical
University of Gdansk, Gdansk, Poland
Keywords: podocytes, diabetes, kidney disease, proteinuria, foot processes, exosomes
Podocytes, glomerular visceral cells of epithelial origin, are the direct target of both immune
and non-immune forms of injury in many diverse glomerular diseases. They do not typically
proliferate in the mature kidney, which means that damaged cells are not replaced by new ones.
It is now generally accepted that dysfunction or loss of these cells underlies progression of almost
all glomerulopathies. Progressing glomerular diseases, of which diabetic nephropathy (DN) is the
most common, are themost frequent cause of end-stage renal disease. Therefore, identification of the
pathways that lead to podocyte injury is essential for developing more effective, targeted therapies.
The articles presented in this research topic give a comprehensive overview of recent discoveries
into the mechanisms of podocyte impairment and discuss the possibilities of podocyte-targeted
therapies.
Each podocyte contacts its neighboring cells via a slit diaphragm (SD) connecting their inter-
digitating foot processes (FPs). Via transmembrane adhesion receptors in the basolateral domain
of the FP, the podocytes interact with the glomerular basement membrane (GBM). Both these
forms of adhesions are crucial for maintaining podocyte structure, which in turn determines
the integrity and permeability of the glomerular filtration barrier. As highlighted by Lennon
et al. (1), the cell–cell and cell–matrix junctions drive the coordinated response of podocytes to
environmental cues in order to regulate glomerular filtration. Recent findings indicate that there
are two distinct FP types, anchoring FPs (AFPs) and ordinary FPs (OFPs), both of which are
involved in the regulation of fluid outflow from the subpodocyte space (2). The components of
SD and adhesion complexes in FPs transduce signals from outside of the podocyte to the actin
cytoskeleton inside the cell. Up to now, almost 100 actin associated proteins have been discovered
in mammalian podocytes, with distribution specific for apical, SD, and basal domains of the FP
membrane (2). Dysregulation of signaling is likely to lead to actin reorganization and podocyte foot
process effacement, which is typically observed in proteinuric diseases. In contrast to traditional
interpretations of this loss of shape as a pathological derangement, Kriz et al. (3) indicate that
adhesions are reinforced in effaced FPs and therefore it seems to be a protective mechanism against
detachment. Alterations in podocyte phenotype and structure are particularly prominent when
proteinuria reaches nephrotic range. It is accepted that loss of the specialized podocyte morphology
is associated with transition from epithelial to a more mesenchymal phenotype irrespective of the
underlying causes that include both genetic defects and mediators from the microenvironment.
However, May et al. (4) note that podocytes display partial features of both mesenchymal and
epithelial cells. Therefore, dependent on the clinical conditions, dedifferentiation in disease could
result in regression to either of these states. Upon treatment, these changes are reversible only if
the insult is not very severe, as for example in minimal change disease (MCD). In focal segmental
glomerulosclerosis (FSGS), phenotypic dedifferentiation of podocytes is not only irreversible but
progressive.
Frontiers in Endocrinology | www.frontiersin.org September 2015 | Volume 6 | Article 1451
Lewko et al. Podocyte pathology and nephropathy
Using a rat model, Kriz et al. (3) have performed a detailed
structural study demonstrating how podocytes reinforce attach-
ment to the GBM and how they detach. It appears that if the
protective mechanisms fail, viable podocytes, mostly in clusters,
detach from the GBM. Some of them may reach the renal pelvis
as living cells, while other may develop contacts to the parietal
epithelium, forming crescents that connect glomerular capillaries
with the Bowman’s capsule. Podocyte depletion represents one
of the earliest cellular lesions affecting the diabetic kidney, and
decreased number of podocytes in glomeruli is the strongest
predictor of progression of both type 1 and 2 DN. Activation of
protein kinase C (PKC) seems to play a critical role in patho-
genesis of DN. Teng et al. (5) point out that conventional as
well as atypical forms of PKC, which play a pivotal role in the
regulation of podocyte physiology, may be a destructive factor
when hyperactivated in disease conditions. PKC activation results
in downregulation of podocyte and SD structural proteins such as
P-cadherin or β-catenin, which may contribute to the disruption
of podocyte integrity. In DN, the PKC isoforms may also mediate
the high glucose-induced overproduction of VEGF and increased
TGFβ signaling in podocytes, with subsequent impairment of the
glomerular filtration barrier. Recent findings reveal that abnormal
intracellular accumulation of sphingolipids modulates podocyte
functions in glomerular disorders of both genetic and non-
genetic origin. Based on their experimental results, Merscher and
Fornoni (6) report that in FSGS, suPAR-dependentαVβ3 integrin
activation decreased expression of sphingomyelin-like phospho-
diesterase 3b (SMPDL3b) resulting in increased accumulation
of sphingomyelin, which is associated with remodeling of the
podocyte actin cytoskeleton, loss of stress fibers, and a shift from
amigratory to an apoptotic phenotype. In contrast, in the diabetic
kidney SMPDL3b expression was elevated, nonetheless render-
ing podocytes more susceptible to apoptosis. These observations
indicate that podocyte responses to sphingolipids are complex and
require additional research.
Hereditary, but also sporadic, nephrotic syndrome (NS) is fre-
quently associated with mutations in podocyte genes encoding
functional and structural proteins. However, currently known
mutations explain <40% of NS cases (7). Moreover, immuno-
suppression appears to be effective in about 8–10% of genetic
disorders. Recent advances in our knowledge about the podocyte
transcriptosome and proteasome have led to identification and
characterization of novel disease-causing variants and disease-
modifying genes. At present, almost 50 podocyte genes directly
associatedwith humanNShave been identified. It has also become
apparent that monogenic defects correlating with some mor-
phological changes in podocytes do not explain completely the
pathogenesis of congenital podocytopathies.
An understanding of the mechanisms of podocyte impairment
will allow for the design of targeted therapeutic approaches that
may prevent deterioration of glomerular function, e.g., in allograft
recipients. The frequency of recurrent as well as newly developed
post-transplant kidney diseases, such as DN, is relatively high and
now it is clear that podocytes are the initial site of injury. Detailed
pathogenesis of post-transplant diabetes is not known; however,
numerous risk factors have been identified (8). Although direct
treatment of genetic disorders still remains a question for the
future, certain biochemical pathways in podocytes already seem
to be a promising target for current therapies. For example, it
has been shown recently that SMPDL3b in podocyte lipid rafts
is a direct target for rituximab, which prevents downregulation
of this protein and podocyte injury (7). Furthermore, calcineurin
inhibitors (CNIs) that, together with glucocorticoids and mTOR
inhibitors, have been traditionally used as anti-inflammatory
agents have been shown to also act directly on podocytes (9).
Diverse actions of CNIs on podocytes include stabilizing the actin
cytoskeleton and inhibitingNFAT-dependent podocyte apoptosis.
Other immunosuppressive drugs, such as abatacept or belatacept,
also directly target the podocytes, suggesting this is an exciting
area for future research (8).
Early, sensitive, and specific diagnosis of ongoing podocyte
injury is still lacking. Microalbuminuria, which results from
podocyte dysfunction, has been accepted as the earliest marker of
DN. However, patients presenting withmicroalbuminuria already
show advanced damage of the glomerular filtration barrier (10),
while nephrinuriamay precede thismanifestation (11). It has been
shown recently that urinary podocyte damage biomarkers corre-
late with cystatin C and eGFR even in normoalbuminuric patients
with type 2 diabetes (11). Yet, due to technical problems, such
as low quantities of podocyte proteins or their proteolytic diges-
tion, using free urinary podocyte proteins as diagnostic markers
appears to be questionable. Musante et al. (12) describe a promis-
ing new method in which exosomes carrying specific podocyte
biomarkers are isolated from urine. In one pilot study, the levels of
urinary exosomal mRNA for cystatin C showed a marked upreg-
ulation after the induction of podocyte damage in the puromycin
aminonucleoside nephrosis (PAN) rat model (13). However, this
was accompanied by the de novo expression of cystatin C not
only in podocytes but also in tubular epithelial cells. On the other
hand, in an experimental model of DN, which is associated with
podocyte injury, cystatin C immunoreactivity in tubules was not
changed (14). So far, there are only few studies referring to the
urinary exosomal mRNA, and data concerning levels and cellular
origin of cystatin CmRNA in urine are still missing. Nevertheless,
correlation between cystatin C and podocyte-specific genes in
urinary exosomes could probably allow for early specific diagnosis
of podocyte damage prior to the symptomatic podocytopathy.
Acknowledgment
BL is supported by Medical University of Gdansk statutory grant
St-54.
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Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Copyright © 2015 Lewko, Welsh and Jankowski. This is an open-access article dis-
tributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution
or reproduction is permitted which does not comply with these terms.
Frontiers in Endocrinology | www.frontiersin.org September 2015 | Volume 6 | Article 1453


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Editorial: Podocyte Pathology and Nephropathy

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