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.