11. Summary
Activation of PARs is responsible for the progression of diabetic
nephropathy. In STZ induced type-1 diabetic mice, thrombin-dependent
PAR1 activation aggravated the progression of diabetic nephropathy and
its inhibition appeared to be nephroprotective. But in the case of
type-2 diabetic kidney diseases, PAR1 inhibition failed to normalize the
kidney dysfunction although it decreased the blood glucose levels.
Strikingly in STZ induced diabetic nephropathic model, deletion of PAR2
led to increased mesangial expansion which happened to be due to
increased compensatory renal PAR1 expression. Notably, Par-2 blockade
was sufficient to attenuate kidney disease in AKITA mice a type-2
diabetes model. It appears that PAR-1 has a direct role in the
regulation of renal perfusion and glomerular filtration rate and thus
interference with its activation might counter the renal hemodynamic
impairments which are encountered in the early period of type-1
diabetes. On the other hand, the PAR-2 receptor is a known regulator of
inflammatory mediators which might be involved in the induction of
glomerular and tubular injury in type-2 diabetes. Therefore inhibition
of PAR-2 can be considered as an effective strategy for ameliorating the
pathogenesis of type-2 diabetic kidney diseases. Though dual PAR
blockade therapy has emerged as a promising therapy, in this case, a
complete understanding of the role of PAR1 and PAR2 in different
diabetic kidney diseases models needs to be done. It has been observed
that in a renal I/R injury model, PAR4 exhibited a dual role, as the
up-regulation of PAR4 exacerbated the I/R induced renal damage while
maintaining the renal filtration barrier. Reasonably these effects might
be explained based upon the distinct physiological and pathological
influences of PAR-4 subtype in kidneys. Notably, both PAR-1 and PAR-2
have proven efficacy against the drug-induced nephrotoxicities in rodent
models but the non-availability of oral inhibitors for PAR-2 and other
subtypes poses a challenge to its translational application in the
management of drug-associated renal injury. Limited evidence also
suggests that targeting the PAR-1/4 subtypes could abolish
experimentally induced podocyte injury but more investigations targeting
other PAR subtypes in these set of diseases are highly desirable.
Lastly, some hope has emerged regarding the anti-inflammatory potential
of PAR-2 blocker therapy against renal inflammation in LPS induced
sepsis model but it failed to improve various renal functional
parameters. Therefore, exploring the protective effects of other PAR
subtypes inhibitors in AKI associated with sepsis is much required.
Nevertheless, it is well evident that PARs have a pivotal role in the
development and progression of diverse renal injuries and once we answer
the existing experimental and therapeutic challenges then their clinical
potential could be unraveled in near future.