Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications

Santhosh Kumar, V.R. et al. (2015) Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications. Journal of the American Society of Nephrology, (doi:10.1681/ASN.2015020208) (PMID:26567242)

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Abstract

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia–induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68+ intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage–derived circulating PAR2 agonist and mediator of endothelial dysfunction–related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Reid, Dr Emma
Authors: Santhosh Kumar, V.R., Darisipudi, M. N., Steiger, S., Devarapu, S. K., Tato, M., Kukarni, O. P., Mulay, S. R., Thomasova, D., Popper, B., Demleitner, J., Zuchtriegel, G., Reichel, C., Cohen, C. D., Lindenmeyer, M. T., Liapis, H., Moll, S., Reid, E., Stitt, A. W., Schott, B., Gruner, S., Haap, W., Ebeling, M., Hartmann, G., and Anders, H.-J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
ISSN:1046-6673
ISSN (Online):1533-3450

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