Protease-activated receptors in diabetic nephropathy and renal fibrosis

In the Netherlands, 1.700.000 people suffer from chronic kidney disease, a condition in which fibrotic tissue builds up in the kidneys. Independent of the underlying cause, chronic kidney disease will slowly progress to end stage renal disease. At that stage, renal replacement therapy by dialysis or transplantation are the only therapeutic options left, which both have a huge social and economic impact. Alternative clinical strategies to prevent the progression of chronic kidney disease are thus eagerly awaited for. As protease-activated receptors recently emerged as key players in fibrosis, the aim of this thesis was to investigate whether protease activated receptors would be good targets for novel interventions that prevent the decay of kidney function in diabetic patients.
As described in this thesis, we found that PAR-1 deficiency protected both diabetic mice and mice suffering from chronic obstructive nephropathy from developing diabetic nephropathy and renal fibrosis, whereas PAR-2 rather acted as a double edged sword resulting in both beneficial and detrimental effects. Based on these results we treated both type 1 and type 2 diabetic mice with the PAR-1 inhibitor vorapaxar. Overall, vorapaxar treatment might be a feasible treatment for type 1 diabetic patients at risk for developing diabetic nephropathy. However, this treatment would be feasible only if bleeding complications associated with vorapaxar treatment are not too severe. Finding the endogenous PAR-1 ligand that potentiates diabetic nephropathy may eventually lead to a treatment strategy that limits diabetic nephropathy without the risk of severe bleedings.