Abstract
Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced 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. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (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 (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), 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 Adenine-induced CKD mice. 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.
Highlights
Chronic kidney disease (CKD) is associated with progressive renal fibrosis as renal function declines
MTORC1 activity in HK-2 cells was significantly increased when 10% serum from CKD patients was added, as compared to 10% serum from healthy subjects. These findings suggested that uremic toxins present in the serum from CKD patients could be involved in mTORC1 activation
We evaluated the effects of seven representative uremic toxins (IS, p-cresyl sulfate (PCS), phenyl sulfate (PS), hippuric acid (HA), indole acetic acid (IA), kynurenic acid (KA), and carboxy-4-methyl5-propyl-2-furanpropanoic acid (CMPF)) on mTORC1 activation in HK-2 cells
Summary
Chronic kidney disease (CKD) is associated with progressive renal fibrosis as renal function declines. A therapeutic strategy targeted to renal fibrosis has become a subject of interest regarding CKD treatment [1]. It has been reported that the inhibition of mTORC1 activity suppresses renal fibrosis in various animal models of renal diseases [5,6,7,8,9,10]. The regulation of renal mTORC1 activity could be a therapeutic target for the treatment of renal fibrosis. It was demonstrated that the constitutive activation of mTORC1, induced by excess energy, persistent oxidative stress, and fibrosis promoting factor (TGF–β), contribute to the development of renal fibrosis [12,13]. The mTORC1 activator and its molecular mechanisms under CKD pathology have still remained unclear
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