8.2 PAR2 mediates glomerular injury and renal dysfunction in
FSGS model
Focal segmental glomerulosclerosis (FSGS) is a glomerular disease that
is manifested as elevated proteinuria, podocyte injury, and immune cell
infiltrations [86]. A study has investigated the role of PAR2 in
mediating focal segmental glomerulosclerosis in drug-induced
nephrotoxicity models [87]. In this study, nephropathy was induced
by giving adriamycin (ADR) intravenously for six weeks which resulted in
elevated PAR2 protein expression in the renal tissues along with the
increased expression of phosphokinase A (PKA) and phosphokinase C (PKC).
Among various signal transduction pathways, PKA and PKC are members of
the cAMP-dependent serine-threonine kinase family that undergoes a
series of phosphorylation and initiates a wide range of intracellular
target proteins [88]. In turn, activation of these enzymes are
likely to be responsible for vascular pathologies along with ECM
synthesis and fibrosis, ROS generation, apoptosis, activation of
monocytes, cell migration, dysregulation of cytokines accelerating
inflammatory cascades in the development of nephropathy [89,90].
Also, past evidence suggests that direct pharmacological inhibition of
PKA and PKC pathways attenuates the progression of renal injuries
[91,92]. Moreover, ADR injection elevated the levels of
pro-inflammatory cytokines in the renal tissues which were significantly
attenuated by blocking PAR2 with FSLLRY-NH2. Notably, the elevated
expression of PKA, PKC, and inflammation was attenuated upon
administration of PAR2 blocker FSLLRY-NH2 (FSL). Furthermore, this study
also suggested that PAR2 activation was involved in increasing the renal
expression of pro-fibrotic TGF-β1, caspase-9 responsible for apoptosis
execution and desmin which is a cytoskeletal muscle-specific protein and
key subunit of type III intermediate filament essential for tensile
strength and structural integrity of myofibrils [93]. In kidneys,
intermediate filament proteins are expressed in glomerular podocytes and
desmin acts as an important marker of podocyte injury and excretion of
this protein reflects heavy proteinuria as well [94,95]. Moreover,
activation of PAR-2 down-regulated podocyte slit-diaphragm structural
protein nephrin expression in the renal tissues of adriamycin injected
rats. Interestingly, it was observed that administration of PAR2 blocker
FSL corrected the levels of these pathological molecular mediators.
Studies have reported that TGF-β1 is a key mediator in renal
inflammation and fibrosis. It also plays key roles in cell
proliferation, differentiation, apoptosis, migration, and ECM production
[96]. In glomerular diseases; TGF-β1 is secreted by mesangial cells
and is stored and transported to the podocyte surface where it is
responsible for mediating inflammation, apoptosis, and podocyte injury
via activating downstream signaling pathways such as Smad, MAPK, ERK,
and PI3K [97-99]. Thus, in the same study, further investigations
were conducted on TGF-β1 treated cultured podocyte cells and it was
observed that there was an increase in the level of the caspase-9
enzyme, indicating podocyte apoptosis along with depleted nephrin and
elevated desmin levels. However, administration of PAR2 blocker in
podocyte cell line has corrected the altered caspase-9, nephrin, and
desmin levels, thus indicating the involvement of PAR2 in mediating the
TGF-β1 induced podocyte damage. Histological studies also showed that
administration of adriamycin has to lead to glomerular injury as
manifested by the expansion of the mesangial matrix. Also in adriamycin
injected rats elevated urinary proteins and serum creatinine levels,
together with increased kidney weight to body weight ratio were noted
which are important markers of glomerular injury and hypertrophy.
However, all these manifestations were attenuated by the administration
of the PAR2 blocker. This study clearly suggested that blocking of PAR2
is beneficial in the prevention of focal segmental glomerulosclerosis by
suppression of pro-inflammatory cytokines release and TGF-β1
inactivation. It is worth mentioning here that presently the treatment
for FSGS relies on ACE inhibitors or ARBs which may not completely block
the development of kidney diseases in FSGS patients [100,101]. Thus
it is important to further investigate the therapeutic potential of PAR2
in other FSGS models.