6.1 Role of PAR1 in progression of diabetic nephropathy
Experimental studies have suggested that PAR1 plays a pivotal role in
diabetic kidney disease, where it is responsible for activation of
fibroblast proliferation and extracellular matrix production resulting
in progression of renal injury [2, 5]. The pathological role of the
PAR1 receptor has been investigated in both type-1 and type-2 diabetic
animal models [5, 12]. In the streptozotocin (STZ) induced type-1
diabetic mice model, the renal expression of PAR1 mRNA was higher in
comparison to non-diabetic mice [4]. Subsequently, this study also
revealed that cultured MES13 (mouse mesangial cells) cells exposed to
high glucose medium showed higher transcripts of PAR1 than low glucose
medium environment exposure. Furthermore, this study showed that in
MES13 addition of thrombin resulted in the mesangial proliferation and
fibronectin production mediated by PAR1 dependent activation of MEK and
p38 signaling pathways. MEK and p38 are important components of the MAPK
signaling pathway [50]. Interestingly, western blot analysis also
showed that their expressions were higher in diabetic rats as compared
to non-diabetic rats [51]. Moreover, studies have documented that
MEK and P38 signaling are activated by high glucose levels, oxidative
stress, and also inflammation and are responsible for various
pathological events including cell proliferation, differentiation, and
apoptosis, which further promote the progression of diabetic nephropathy
[50,51]. Notably, in STZ induced type-1 diabetic mice model, the
fibrin-mediated mesangial proliferation was abolished upon
co-administration of PAR1 antagonist (p1pal-12) or by direct inhibition
of MEK/p38 signaling indicating that thrombin and PAR1 are interlinked
in the development of glomerular injury. Additionally,
immunohistochemical evidence from PAR1 deficient diabetic mice showed a
reduction in mesangial expansion, proliferation, fibronectin deposition,
and also the absence of tubular atrophy compared to wild-type (WT)
diabetic mice. Moreover, in WT diabetic mice increased plasma cystatin C
levels and also proteinuria was observed due to hyperglycemia-induced
hyperfiltration, podocyte apoptosis, and glomerular filtration barrier
damage. So far studies have reported that the generation of plasma
thrombin (PAR1 agonist) is increased in patients suffering from diabetes
[52-54]. This evidence suggests that inhibition of thrombin-mediated
PAR1 activation could be a novel therapeutic target for the prevention
of type-1 diabetic nephropathy.
Another experimental study has tested the pathological involvement of
PAR1 in the development of type-2 diabetic nephropathy [12].
BTBRob/ob mice are leptin-deficient obese mice that
served as a diabetic group, whereas wild types (WT) are considered as a
non-diabetic control group. BTBRob/ob diabetic mice
were treated with vorapaxar, a PAR1 antagonist which produced an
increased body weight. In this study, the type-2 diabetic mice exhibited
renal pathological changes such as increased kidney weight, albuminuria,
neutrophil-gelatinase-associated lipocalin (NGAL) excretion, and also
increased plasma insulin levels. Moreover, BTBRob/obdiabetic mice showed glomerular injury with mesangial expansion,
capillary dilation, and glomerulosclerosis. Notably, vorapaxar treatment
did not correct the glomerular damage, but mesangial expansion was
significantly reduced in comparison to non-treated diabetic
BTBRob/ob mice. During the disease progression in
BTBRob/ob mice, diabetic nephropathy was accompanied
by inflammation as illustrated by increased IL-6, IL-1β, TNF-α, and
MCP-1 in both vorapaxar treated and non treated diabetic mice.
Importantly, these findings are in contrast to a previous study in which
inhibition of PAR1 receptor prevented nephropathy in type 1 diabetes
model [55]. The most reasonable explanation for distinct outcomes
observed due to PAR1 blockade in the above studies could be based upon
etiological differences in the development of type 1 and type 2 diabetic
kidney diseases. In diabetic nephropathy, both hemodynamic and
structural changes are interlinked with each other. Studies showed that
in type-1 diabetic nephropathy, the earliest hemodynamic abnormality
observed is renal hyperfiltration which leads to increased
intra-glomerular pressure, followed by glomerular injury with podocyte
effacement and also tubular dilation. These pathological events are also
accompanied by microalbuminuria and a progressive decline in glomerular
filtration rate (GFR) [56]. However, type-2 diabetic nephropathy is
an inflammatory prominent disease, where other pathogenic factors
including obesity, hypertension with compensatory hyperinsulinemia could
exacerbate the metabolic disturbance [57]. Moreover, renal
hypertrophy is observed post-development of glomerulosclerosis and
tubulointerstitial fibrosis in DN (diabetic nephropathy). Of note,
hemodynamic changes are commonly observed in both type 1 and 2 DN
patients [58]. Thus it might be possible that PAR 1 inhibition could
not influence the pathological manifestations accompanying the type-2 DN
due to the complex etiological basis of this disease type. However, in
type 1 DN, the PAR 1 inhibition exhibited renoprotection by improving
renal dysfunction and ameliorating proliferative changes in glomerular
regions.