title: Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease.
abstract: During chronic kidney disease (CKD) there is a dysregulation of extracellular matrix (ECM) homeostasis leading to renal fibrosis. Lysosomal proteases such as cathepsins (Cts) regulate this process in other organs, however, their role in CKD is still unknown. Here we describe a novel role for cathepsins in CKD. CtsD and B were located in distal and proximal tubular cells respectively in human disease. Administration of CtsD (Pepstatin A) but not B inhibitor (Ca074-Me), in two mouse CKD models, UUO and chronic ischemia reperfusion injury, led to a reduction in fibrosis. No changes in collagen transcription or myofibroblasts numbers were observed. Pepstatin A administration resulted in increased extracellular urokinase and collagen degradation. In vitro and in vivo administration of chloroquine, an endo/lysosomal inhibitor, mimicked Pepstatin A effect on renal fibrosis. Therefore, we propose a mechanism by which CtsD inhibition leads to increased collagenolytic activity due to an impairment in lysosomal recycling. This results in increased extracellular activity of enzymes such as urokinase, triggering a proteolytic cascade, which culminates in more ECM degradation. Taken together these results suggest that inhibition of lysosomal proteases, such as CtsD, could be a new therapeutic approach to reduce renal fibrosis and slow progression of CKD.
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fox
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Cocchiaro
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Howarth
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Krystena
authors.initials: K
authors.lastname: Callaghan
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Leslie
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Saimir
authors.initials: S
authors.lastname: Luli
authors.affiliation: Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Wood
authors.affiliation: Nordic Bioscience, 2730 Herlev, Denmark.
authors.forename: Federica
authors.initials: F
authors.lastname: Genovese
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Sheerin
authors.affiliation: Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Moles
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D008247:Lysosomes / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000201:enzymology / Q000473:pathology; D010436:Pepstatins / Q000494:pharmacology*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
chemical_list: C400541:CA 074 methyl ester; D004151:Dipeptides; D010436:Pepstatins; D002738:Chloroquine; D003094:Collagen; D002402:Cathepsin D; C533923:Ctsd protein, mouse; C031375:pepstatin
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