Novel Insight Into the Pathogenesis of Nephrotic Syndrome
Albert Einstein College of Medicine
New York, NY
Podocytes are important for glomerular biology and pathology. Podocytes are terminally differentiated
cells that line the outer aspect of the glomerular basement membrane. Podocytes therefore forms the
final barrier to protein loss, which explains why podocyte injury is typically associated with marked
proteinuria. Podocytes are highly differentiated cells with limited capability to undergo cell division
in the adult. Their function is largely based on complex cell architecture loss of podocytes is a
hallmark of progressive renal disease  . Podocytes play a key role in the development and progression
of most glomerular diseases including Minimal change disease, Congenital Nephrotic Syndrome, Familial and
Secondary FSGS, Denys-Drash Syndrome, Frasier Syndrome, Diabetic nephropathy, Chronic
glomerulonephritis, Collapsing idiopathic glomerulopathy and HIV-asociated glomerulopathy  . The
podocyte slit diaphragm is dynamic site of glomerular permselectivity. The SD represents is made up of
rod-like units connected in the center to a linear bar forming a zipper like appearance and is organized
in lipid rafts. The recent discovery of several SD proteins and their mutation analysis including
nephrin, the nephrin homologue(s) neph1(-3), CD2AP, podocin, and the protocadherin FAT shed light on the
pathogenesis of proteinuria . These findings emphasized the critical role of the SD for the function of
the glomerular filtration barrier. In addition to the SD, it has become clear that the podocyte actin
cytoskeleton plays a central integrative role in the regulation of glomerular filtration and for the
progression to ESRD  .
Podocyte foot processes (FP) are defined by three membrane domains - the apical membrane domain, the
SD protein complex and the basal membrane domain or sole plate. All three compartments are linked to the
FP actin cytoskeleton. The FP actin cytoskeleton is highly dynamic as shown in the acute PS/heparin
model of reversible FP effacement. Interference with one of the three domains changes the actin
cytoskeleton from coordinated parallel bundles into a dense network with FP effacement and obliteration
of filtration slits. Proteins regulating or stabilizing F-actin like α-actinin-4 or synaptopodin are
therefore of critical importance for sustained function of glomerular filtration  . Podocytes of a3
integirn deficient (a3-/-)mice are unable to maintain normal podocyte structure, including the
elaboration of mature foot processes along the GBM  . To identify genes critically involved in the
development of FP effacement and proteinuria, we performed a genomic screen comparing wild type and a
3-/- podocytes. With this approach we uncovered a unanticipated novel role for B7-1 in
podocytes as inducible modifier of glomerular permselectivity  . B7-1 in podocytes was found in
genetic, drug-induced, immune-mediated and bacterial toxin-induced experimental kidney diseases with
nephrotic syndrome  . The clinical significance of our results is underscored by the observation that
podocyte expression of B7-1 correlated with the severity of human lupus nephritis. LPS signaling through
TLR-4 re-organized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes
led to reorganization of vital slit diaphragm proteins  . In vivo, LPS rapidly upregulated B7-1 in
podocytes of wild type and SCID mice leading to nephrotic range proteinuria. Mice lacking B7-1 were
protected from LPS-induced nephrotic syndrome. Take together these data established a causal link
between podocyte B7-1 expression and urinary protein loss that is independent of lymphocyte infiltration
or activation  . It has not escaped out attention that LPS induced nephrotic syndrome shares several
key features of human MCD in that the FP effacement and proteinuria are transient and present without
signs of glomerular inflammation. The upregulation of B7-1 in podocytes suits well to provide a unifying
molecular explanation for the pathogenesis of proteinuria in nephrotic syndrome. However, it is
difficult to believe that the sole (and harmful) function of podocyte B7-1 should be to disassemble the
glomerular filter. Hence, it is intriguing to speculate that transient B7-1 dependent proteinuria may be
a physiological response that is desirable under certain conditions, e.g. in patients with gram-negative
infection. The disruption of the glomerular filter by TLR-induced B7-1 may help the innate immune system
in clearing the circulation from harmful agents by dumping them into the urine the urine. In this
scenario, the transient urinary protein loss would be the price that we pay
for the rapid decay of the harmful agent. Consistent with this idea, the development of transient
proteinuria has been found during the course of gram negative sepsis  . Moreover, a prospective study
showed that in postoperative septic patients microalbuminuria is an early indicator of increased
glomerular permeability, but not in non-septic patients  . Clearly, this is highly speculative and
future studies will be required to explore this hypothesis in detail. In MCD, the onset of nephrotic
syndrome is often preceded by an infection or allergic reaction  . Some children present with fever
and bacteremia. In a number of these patients, the peritoneal cavity is the site of the infection and
Streptococcus pneumoniae, Staphylococcus aureus
and Escherichia coli are commonly isolated  . A urinary tract infection
is occasionally present and a history of upper respiratory tract infection immediately preceding the
first clinical signs of nephrotic syndrome may exist and stimulate the activation of podocyte danger
signaling pathways, thereby leading to B7-1 induced nephrotic syndrome. This raises the intriguing
possibility that prolonged nephrotic syndrome in MCD may result from the persistence of a normally
beneficial response caused by genetic defects in the B7-1 pathway or by the persistence of other
unphysiological activators of podocyte B71. The sustained B7-1 activation in podocytes, in turn, may
result in the continuation or recurrence of nephrotic syndrome in this setting.
The activation of the innate immune system by LPS 
(and potentially other pathogen associated
particles) leads to the upregulation of podocyte B7-1. In the light of these results is tempting to
speculate that podocyte B7-1 may not only act to reorganize the slit diaphragm but participate in the
activation of circulating T-cells. Under normal conditions T-cells are unable to enter the glomerulus
but in advanced stages of nephrotic syndrome, it may be facilitated for T-cells to enter Bowman's space
and directly interact with podocytes. A podocyte-T-cell interaction may result in stimulation and
activation of T-cells. In inflammatory glomerulonephritis, T-cells can be found in the glomerulus in
Bowman's space and B7-1 as well as B7-2 regulate crescentic glomerulonephritis  . Therefore, podocyte
B7-1 may also modulate T-cell-mediated cytotoxicity in immune and nonimmune kidney diseases with
proteinuria. The expression of B7-1 by podocytes in glomerulonephritic situations may serve to recruit
T-cells to sites of GBM damage and breakdown, and promote further inflammation  . In summary, taking
advantage of our increasing molecular knowledge about the role of podocytes in the pathogenesis of
Nephrotic Syndrome, it should be possible to development of "podocyte-protective" drugs. Such
podocyte-specific drugs may promote SD protein expression/localization/function, promote recovery from
foot process effacement and Prevent detachment/loss of podocytes.
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