Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 151, Issue 2, Pages 72-83Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1016/j.jphs.2022.12.001
Keywords
Unilateral ureteral obstruction; Calycosin; Mesenchymal stem cells; Renal fibrosis; Necroptosis
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In this study, the researchers found that Calycosin, a phytoestrogen, can enhance the antifibrotic activity of bone marrow-derived mesenchymal stem cells (MSCs) in primary tubular epithelial cells and a mouse model of unilateral ureteral obstruction. It achieves this by inhibiting necroptosis induced by TGF-b1/TNF-a/TNFR1 signaling.
Bone marrow-derived mesenchymal stem cells (MSCs) show antifibrotic activity in various chronic kidney diseases. Here, we aimed to investigate whether Calycosin (CA), a phytoestrogen, could enhance the antifibrotic activity of MSCs in primary tubular epithelial cells (PTECs) induced by TGF-b1 and in a mouse model of unilateral ureteral obstruction (UUO). We found that MSCs treatment significantly inhibited fibrosis, and CA pretreatment enhanced the effects of MSCs on fibrosis in vitro. Consistent with the in vitro studies, MSCs alleviated tubular injury and renal fibrosis in mice after UUO, and CA pretreated MSCs resulted in more significant improvements in tubular injury and renal fibrosis than MSCs after UUO. Moreover, MSCs treatment significantly inhibited necroptosis by repressing the elevation of MLKL, RIPK1, and RIPK3 in PTECs treated by TGF-b1and in mice after UUO, and CA-pretreated MSCs were superior to MSCs in alleviating necroptosis. MSCs significantly reduced TNF-a and TNFR1 expression induced by TGF-b1 in PTECs and inhibited TGF-b1, TNF-a, and TNFR1 expression induced by UUO in mice. These effects of MSCs were significantly enhanced after CA pretreatment. Therefore, our results suggest that CA pretreatment enhances the antifibrotic activity of MSCs by inhibiting TGF-b1/TNF-a/TNFR1 signaling-induced necroptosis.(c) 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/lice nses/by-nc-nd/4.0/).
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