Cathepsin S regulates renal fibrosis in mouse models of mild and severe hydronephrosis

Abstract

As a member of the cysteine protease family, cathepsin S (CTSS) serves an important role in diseases such as cancer, arthritis and atherosclerosis. Nevertheless, its role in renal fibrosis is unknown. In the present study, the effects of CTSS on renal fibrosis in mild (group M) and severe (group S) hydronephrosis were studied by reverse transcription-quantitative PCR (RT-qPCR), western blot analysis (WB), Masson's trichrome staining and immunohistochemical staining in mouse models. The effects of CTSS on extracellular matrix (ECM) deposition and epithelial-mesenchymal transition (EMT) and the potential mechanisms were further studied by RT-qPCR and WB in transforming growth factor (TGF-β1)-stimulated TCMK-1 cells. Compared with group N (no hydronephrosis), the expression levels of CTSS in the M and S groups were significantly higher, and a significant increase in ECM deposition was observed in the S group. In addition, compared with group N, the expression levels of TGF-β1, α-smooth muscle actin (α-SMA), SMAD2, SMAD3, phosphorylated (p)SMAD2 and pSMAD3 in groups M and S were significantly higher, whereas the expression of E-cadherin was significantly lower. Inhibition of CTSS expression increased the expression levels of TGF-β1, α-SMA, fibronectin, collagen-I, SMAD2, SMAD3, pSMAD2 and pSMAD3, whereas E-cadherin expression decreased. A significant increase in CTSS was observed in the TGF-β1-stimulated TCMK-1 cell line. ECM deposition and EMT were also intensified. The opposite outcomes occurred after intervention with small interfering RNA targeting CTSS. In conclusion, CTSS affected EMT and the deposition of ECM. CTSS may mediate the regulation of fibrosis by the TGF-β/SMAD signaling pathway. CTSS may serve an important role in the treatment of renal fibrosis.

Urine peptidome analysis in cardiorenal syndrome reflects molecular processes

“…Levels of the mRNA, protein and activity of CTSS were found increased in the left ventricular myocardium of humans and rats with HF compared with controls, suggesting its participation in cardiac remodeling 65 . CTSS was also shown to affect epithelial-to-mesenchymal transition and ECM deposition in mouse models of mild and severe hydronephrosis, indicating its role in the regulation of renal fibrosis 66 .…”

Identification of Hub Genes and Immune-Related Pathways for Membranous Nephropathy by Bioinformatics Analysis

“…CTSS increases microvascular permeability and leukocyte adhesion during inflammation by activating protease-activated receptor (PAR)-2 on endothelial cells, leading to endothelial dysfunction (Steubl et al, 2017). Yao et al have confirmed that CTSS mediated the regulation of renal fibrosis through the transforming growth factor-β/SMAD signaling pathway (Yao et al, 2019). As GFR decreased, CTSS and markers of endothelial dysfunction associated with inflammation, such as soluble tumor-necrosis-factor receptors (sTNFR) 1 and 2, increased (Steubl et al, 2017) and might be crucial to MN pathogenesis.…”

Proteomics changes after negative pressure wound therapy in diabetic foot ulcers

“…It participates in the degradation of antiangiogenic peptides and adhesion proteins and promotes neovascularization and tumor cell invasion and metastasis ( 62 ). Previous studies found that CTSS can interact with MMPs and serine proteases and participates in the degradation of the ECM ( 63 , 64 ). An important physiological feature of the healing process after tissue injury is increased ECM synthesis and aggregation surrounding the wound.…”