Abstract
SummaryTransforming growth factor beta (TGF-β) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-β enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-β expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the importin-β and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-β receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-β receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-β signaling and tissue fibrosis. CatB- or CatL-deficiency exacerbates fibrosis, whereas CatS- or CatK-deficiency protects kidneys from fibrosis. These cathepsins exert different effects in the TGF-β signaling cascade independent of their proteolytic properties.
Highlights
Transforming growth factor beta (TGF-b), a pleiotropic mediator of fibrotic remodeling, induces myofibroblast transition, Smad activation, and extracellular matrix (ECM) production; inhibits excessive ECM protein degradation by regulation of proteases and their endogenous inhibitors; and regulates integrin expression and cell adhesion to the matrix (Border and Noble, 1994; Lan, 2003)
Kidney tubular epithelial cells (TECs) were isolated from wild-type (WT), Ctsb–/, Ctsl–/, Ctss–/, and Ctsk–/– mice and characterized by immunofluorescent staining for the epithelial marker E-cadherin and for the proximal tubule epithelial cell marker aquaporin-1 (Figure S1A)
transforming growth factor (TGF)-b promoted acquisition of a fibrotic phenotype by TECs characterized by reduced E-cadherin expression and increased a-smooth muscle actin (a-SMA) expression (Figure S1C)
Summary
Transforming growth factor beta (TGF-b), a pleiotropic mediator of fibrotic remodeling, induces myofibroblast transition, Smad activation, and extracellular matrix (ECM) production; inhibits excessive ECM protein degradation by regulation of proteases and their endogenous inhibitors; and regulates integrin expression and cell adhesion to the matrix (Border and Noble, 1994; Lan, 2003). Lung epithelial cell-specific depletion of TGFBR2 protects mice from bleomycin-induced fibrosis (Li et al, 2011). Continued TGF-b activation promotes chronic hypertension, progressive myocardial fibrosis, and heart failure. Infarcted hearts from Smad-3-deficient mice show reduced fibrosis (Bujak et al, 2007), and fibroblasts from these mice do not respond to TGF-b (Verrecchia et al, 2001). Chronic liver damage-induced TGF-b activates hepatic stellate cell (HSC)-to-myofibroblast transition and hepatocyte death and promotes liver fibrosis, cirrhosis, and hepatocellular carcinoma (Dongiovanni et al, 2014). TGF-b1 induces tubular epithelial cell (TEC)-tomyofibroblast transition and promotes renal fibrosis (Lan, 2003)
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