{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:54:06Z","timestamp":1790650446503,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>\n                    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.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    microscopy confirmed a role for intrinsic Cat-S\/PAR2 in ischemia\u2013induced microvascular permeability.\n                    <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\u2013derived circulating PAR2 agonist and mediator of endothelial dysfunction\u2013related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.\n                  <\/jats:p>","DOI":"10.1681\/asn.2015020208","type":"journal-article","created":{"date-parts":[[2015,11,13]],"date-time":"2015-11-13T22:04:42Z","timestamp":1447452282000},"page":"1635-1649","source":"Crossref","is-referenced-by-count":71,"title":["Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications"],"prefix":"10.1681","volume":"27","author":[{"given":"Santhosh","family":"Kumar VR","sequence":"first","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murthy N.","family":"Darisipudi","sequence":"additional","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, Munich, 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Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrikant R.","family":"Mulay","sequence":"additional","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Thomasova","sequence":"additional","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Popper","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Ludwig-Maximilians Universit\u00e4t, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Demleitner","sequence":"additional","affiliation":[{"name":"Walther-Straub-Institut for Pharmakologie und Toxikologie,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Zuchtriegel","sequence":"additional","affiliation":[{"name":"Walter Brendel Centre of Experimental Medicine, and"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Reichel","sequence":"additional","affiliation":[{"name":"Walter Brendel Centre of Experimental Medicine, and"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens D.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Krankenhaus Harlaching, Munich, Germany;"},{"name":"Division of Nephrology and Institute of Physiology, University Hospital and University of Zurich, Zurich, 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