title: Circulating cathepsin-S levels correlate with GFR decline and sTNFR1 and sTNFR2 levels in mice and humans.
abstract: Cardiovascular complications determine morbidity/mortality in chronic kidney disease (CKD). We hypothesized that progressive CKD drives the release of cathepsin-S (Cat-S), a cysteine protease that promotes endothelial dysfunction and cardiovascular complications. Therefore, Cat-S, soluble tumor-necrosis-factor receptor (sTNFR) 1/2 and glomerular filtration rate (GFR) were measured in a CKD mouse model, a German CKD-cohort (MCKD, n = 421) and two Swedish community-based cohorts (ULSAM, n = 764 and PIVUS, n = 804). Association between Cat-S and sTNFR1/2/GFR was assessed using multivariable linear regression. In the mouse model, Cat-S and sTNFR1/2 concentrations were increased following the progressive decline of GFR, showing a strong correlation between Cat-S and GFR (r = -0.746, p < 0.001) and Cat-S and sTNFR1/sTNFR2 (r = 0.837/0.916, p < 0.001, respectively). In the human cohorts, an increase of one standard deviation of estimated GFR was associated with a decrease of 1.008 ng/ml (95%-confidence interval (95%-CI) -1.576-(-0.439), p < 0.001) in Cat-S levels in MCKD; in ULSAM and PIVUS, results were similar. In all three cohorts, Cat-S and sTNFR1/sTNFR2 levels were associated in multivariable linear regression (p < 0.001). In conclusion, as GFR declines Cat-S and markers of inflammation-related endothelial dysfunction increase. The present data indicating that Cat-S activity increases with CKD progression suggest that Cat-S might be a therapeutic target to prevent cardiovascular complications in CKD.
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Steubl
authors.affiliation: Medizinische Klinik und Poliklinik IV, Renal Division, Klinikum der Universität München, Campus Innenstadt, München, Germany.
authors.forename: Santhosh V
authors.initials: SV
authors.lastname: Kumar
authors.affiliation: Medizinische Klinik und Poliklinik IV, Renal Division, Klinikum der Universität München, Campus Innenstadt, München, Germany.
authors.forename: Maia
authors.initials: M
authors.lastname: Tato
authors.affiliation: Medizinische Klinik und Poliklinik IV, Renal Division, Klinikum der Universität München, Campus Innenstadt, München, Germany.
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Departments of Public Health and Caring Sciences/Clinical Nutrition, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Risérus
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Renders
authors.affiliation: Abteilung für Nephrologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.|Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Axel C
authors.initials: AC
authors.lastname: Carlsson
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.|School of Health and Social Studies, Dalarna University, Falun, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ärnlöv
authors.affiliation: Medizinische Klinik und Poliklinik IV, Renal Division, Klinikum der Universität München, Campus Innenstadt, München, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D002403:Cathepsins / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D005858:Germany; D005919:Glomerular Filtration Rate; D020662:Guanine Nucleotide Exchange Factors / Q000097:blood*; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008875:Middle Aged; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D012307:Risk Factors; D013548:Sweden
chemical_list: D015415:Biomarkers; D020662:Guanine Nucleotide Exchange Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D002403:Cathepsins; C028217:cathepsin S