Abstract
TGF-β signaling, Smad activation, and extracellular matrix (ECM) production contribute to tissue fibrosis. Here we demonstrate that TGF-β enhances the expression of cysteinyl cathepsins CatS and CatK, but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). TECs from Ctss-/- and Ctsk-/- mice show reduced expression of nuclear membrane importer protein importin-β, Smad-2/3 activation, and ECM production, yet those from Ctsb-/- and Ctsl-/- mice display increased importin-I² expression, Smad-2/3 activation, and ECM production, but reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the nuclear membrane 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, while in contrast 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. TECs in fibrotic tissues exhibit decreased CatB and CatL, but increased CatS and CatK activities. CatB- or CatL-deficiency exacerbates fibrosis, while CatS- or CatK-deficiency protects kidneys from fibrosis. These results shed novel mechanistic insight into how these closely related cysteinyl cathepsins can exert opposing effects in the TGF-β signaling cascade independent of their proteolytic properties. Funding: This work is supported by grants from the National Institute of Health [HL080472 to PL, HL123568 and HL60942 to GPS], and the RRM Charitable Fund to PL. Declaration of Interest: The authors have declared no conflicts of interest. Ethical Approval: All animal procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health and were approved by the Harvard Medical School Standing Committee on Animals (protocol #03759).
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