The Uremic Toxin Indoxyl Sulfate Contributes to Renal Fibrosis via mTORC1 Signaling Pathway

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Background: Activation of mTORC1 in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. This suggests that the regulation of renal mTORC1 activity represents a potential therapeutic target for the treatment of renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Methods: Human renal proximal tubule epithelial cells (HK-2 cells), rat renal interstitial fibroblast (NRK-49F cells), and human monocytes (THP-1 cells) were used in in vitro studies. Adenine-induced CKD mice were used in in vivo studies. Results: Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS), an indole-containing compound, caused significant activation of mTORC1 in HK-2 cells. This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial-mesenchymal transition of tubular epithelial cells, differentiation of fibroblasts into myofibroblasts, and inflammatory response of macrophages, which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS-overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in CKD mice. Conclusions: The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD. Funding: Government Support - Non-U.S.

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