Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications.

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.

• Authors: Santhosh Kumar Vr, Murthy N Darisipudi, Stefanie Steiger, Satish Kumar Devarapu, Maia Tato, Onkar P Kukarni, Shrikant R Mulay, Dana Thomasova, Bastian Popper, Jana Demleitner, Gabriele Zuchtriegel, Christoph Reichel, Clemens D Cohen, Maja T Lindenmeyer, Helen Liapis, Solange Moll, Emma Reid, Alan W Stitt, Brigitte Schott, Sabine Gruner, Wolfgang Haap, Martin Ebeling, Guido Hartmann, Hans-Joachim Anders
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 27 Issue 6 Pg. 1635-49 (06 2016) ISSN: 1533-3450 [Electronic] United States
• PMID: 26567242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• RO5461111
• Receptor, PAR-2
• Proline
• Cathepsins
• cathepsin S

Topics

• Animals
• Cathepsins (antagonists & inhibitors, physiology)
• Cells, Cultured
• Diabetic Angiopathies (etiology)
• Endothelial Cells (enzymology)
• Kidney Glomerulus (cytology)
• Male
• Mice
• Microvessels
• Proline (analogs & derivatives, pharmacology)
• Receptor, PAR-2 (metabolism)
• Urothelium (cytology)