title: 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.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Santhosh
authors.initials: S
authors.lastname: Kumar Vr
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Murthy N
authors.initials: MN
authors.lastname: Darisipudi
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Steiger
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Satish Kumar
authors.initials: SK
authors.lastname: Devarapu
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Maia
authors.initials: M
authors.lastname: Tato
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kukarni
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany;
authors.forename: Dana
authors.initials: D
authors.lastname: Thomasova
authors.affiliation: Department of Anatomy and Cell Biology, Ludwig-Maximilians Universität, Munich, Germany;
authors.forename: Bastian
authors.initials: B
authors.lastname: Popper
authors.affiliation: Walther-Straub-Institut for Pharmakologie und Toxikologie.
authors.forename: Jana
authors.initials: J
authors.lastname: Demleitner
authors.affiliation: Walter Brendel Centre of Experimental Medicine, and Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, Munich, Germany;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zuchtriegel
authors.affiliation: Walter Brendel Centre of Experimental Medicine, and Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, Munich, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Reichel
authors.affiliation: Division of Nephrology, Krankenhaus Harlaching, Munich, Germany; Division of Nephrology and Institute of Physiology, University Hospital and University of Zurich, Zurich, Switzerland;
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.affiliation: Institute of Clinical Pathology, University Hospital Geneva, Geneva, Switzerland;
authors.forename: Solange
authors.initials: S
authors.lastname: Moll
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Ireland; and.
authors.forename: Emma
authors.initials: E
authors.lastname: Reid
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Ireland; and.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
authors.affiliation: Cardiovascular and Metabolism, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schott
authors.affiliation: Cardiovascular and Metabolism, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gruner
authors.affiliation: Cardiovascular and Metabolism, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haap
authors.affiliation: Cardiovascular and Metabolism, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Cardiovascular and Metabolism, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, Munich, Germany; hjanders@med.uni-muenchen.de.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology*; D042783:Endothelial Cells / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000166:cytology; D008297:Male; D051379:Mice; D055806:Microvessels; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000378:metabolism*; D019459:Urothelium / Q000166:cytology
chemical_list: C000596028:RO5461111; D044464:Receptor, PAR-2; D011392:Proline; D002403:Cathepsins; C028217:cathepsin S
keywords: albuminuria; diabetic nephropathy; endothelial cells; macrophages