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

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 GrunerWolfgang Haap, Martin Ebeling, Guido Hartmann, Hans-Joachim Anders

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1635-1649
Number of pages14
JournalJournal of the American Society of Nephrology
Volume27
Issue number6
Early online date13 Nov 2015
DOIs
Publication statusPublished - Jun 2016

Bibliographical note

Copyright © 2015 by the American Society of Nephrology.

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