Plasmin reduces fibronectin deposition by mesangial cells in a protease-activated receptor-1 independent manner |
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Authors: | Maaike Waasdorp JanWillem Duitman C. Arnold Spek |
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Affiliation: | 1. Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands;2. INSERM, UMR1152, Medical School Xavier Bichat, Paris, France;3. Paris Diderot University, Sorbonne Paris Cité, Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation and Remodeling), LabEx Inflamex, Paris, France |
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Abstract: | BackgroundProtease-activated receptor-1 (PAR-1) potentiates diabetic nephropathy (DN) as evident from reduced kidney injury in diabetic PAR-1 deficient mice. Although thrombin is the prototypical PAR-1 agonist, anticoagulant treatment does not limit DN in experimental animal models suggesting that thrombin is not the endogenous PAR-1 agonist driving DN.ObjectivesTo identify the endogenous PAR-1 agonist potentiating diabetes-induced nephropathy.MethodsUnbiased protease expression profiling in glomeruli from human kidneys with DN was performed using publically available microarray data. The identified prime candidate PAR-1 agonist was subsequently analysed for PAR-1-dependent induction of fibrosis in vitro.ResultsOf the 553 proteases expressed in the human genome, 247 qualified as potential PAR-1 agonists of which 71 were significantly expressed above background in diabetic glomeruli. The recently identified PAR-1 agonist plasmin(ogen), together with its physiological activator tissue plasminogen activator, were among the highest expressed proteases. Plasmin did however not induce mesangial proliferation and/or fibronectin deposition in vitro. In a PAR-1 independent manner, plasmin even reduced fibronectin deposition.ConclusionExpression profiling identified plasmin as potential endogenous PAR-1 agonist driving DN. Instead of inducing fibronectin expression, plasmin however reduced mesangial fibronectin deposition in vitro. Therefore we conclude that plasmin may not be the endogenous PAR-1 agonist potentiating DN. |
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Keywords: | PAR-1 Diabetic nephropathy Plasmin Protease profiling |
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