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.

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

“…A recent study showed that NR3C2 is downregulated in stable and chronic rejection (CR) patients compared with kidneytransplant recipients with "operational tolerance" [47]. CTSS, also known as cathepsin S, is a lysosomal cysteine proteinase that may participate in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules; in addition, circulating cathepsin S levels are associated with GFR decline in mice and humans [48], and specific inhibition of cathepsin S could diminish the effects of cardiovascular disease (CVD), especially in patients with CKD [49]. Still, only few co.DEGs have been reported in association with CKD to date, especially for their roles in podocyte damage.…”

The Multifaceted Role of the Lysosomal Protease Cathepsins in Kidney Disease

“…Kidney disease (Luhe et al, 2003 ; Aikawa et al, 2009 ; Carlsson et al, 2015 ; Figueiredo et al, 2015 ; Steubl et al, 2017 )…”

Decreased serum cathepsin S levels in patients with systemic sclerosis‐associated interstitial lung disease

“…In this study, we interpreted that the inverse correlation of serum CTSS levels with eGFR in patients with eGFR of less than 60 min/mL per 1.73 m 2 was due to the decrease in a renal clearance of circulating CTSS because CTSS has a similar molecular weight to several markers of glomerular filtration, including cystatin C, b-trace protein and b2-microglobulin. 24 However, we could not exclude the possibility that CTSS is involved in the development of kidney involvement associated with SSc, including SRC. Indeed, CTSS released from activated monocytes and neutrophils into circulation is believed to play a part in endothelial dysfunction by activating proteaseactivated receptor 2.…”

“…Because serum CTSS levels inversely correlate with eGFR in patients with chronic kidney disease and a murine model of progressive chronic kidney disease, 24 we first assessed the influence of renal function on serum CTSS levels in SSc patients. To this end, we classified SSc patients into two groups according to eGFR and evaluated the correlation of serum CTSS levels with eGFR in each group.…”