TGF-β-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury

Jeong, Bo Young; Park, Se-Ra; Cho, Sung-Kwon; Yu, Seong‐Lan; Lee, Hoi Young; Park, Chang Gyo; Kang, Jaeku; Jung, Da-Young; Park, Moon Hyang; Hwang, Won‐Min; Yun, Sung-Ro; Jung, Ju‐Young; Yoon, Se-Hee

doi:10.1093/jac/dkx479

Cited by 35 publications

(43 citation statements)

References 46 publications

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“…Accumulated studies have demonstrated that TGF-β1 stimulated the production of ROS in various cell types, which in turn activated TGF-β and mediated many fibrogenic effects. Some studies have shown that TGF-β/Smad signaling plays a vital role in oxidative stress [23]. We investigated the relationship between TGF-β/Smad signaling and oxidative stress in PMCs; however, LY2109761 treatment did not decrease ROS production, indicating that TGF-β1-induced ROS in HPMCs does not depend on TGF-β/Smad signaling.…”

Section: Discussionmentioning

confidence: 86%

Asiaticoside inhibits TGF-β1-induced mesothelial-mesenchymal transition and oxidative stress via the Nrf2/HO-1 signaling pathway in the human peritoneal mesothelial cell line HMrSV5

et al. 2020

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Background: Peritoneal fibrosis (PF) is a frequent complication caused by peritoneal dialysis (PD). Peritoneal mesothelial cells (PMCs), the first barrier of the peritoneum, play an important role in maintaining structure and function in the peritoneum during PD. Mesothelial-mesenchymal transition (MMT) and oxidative stress of PMCs are two key processes of PF. Purpose: To elucidate the efficacy and possible mechanism of asiaticoside inhibition of MMT and ROS generation in TGF-β1-induced PF in human peritoneal mesothelial cells (HPMCs). Methods: MMT and ROS generation of HPMCs were induced by TGF-β1. To explain the anti-MMT and antioxidant role of asiaticoside, varied doses of asiaticoside, oxygen radical scavenger (NAC), TGF-β receptor kinase inhibitor (LY2109761) and Nrf2 inhibitor (ML385) were used separately. Immunoblots were used to detect the expression of signaling associated proteins. DCFH-DA was used to detect the generation of ROS. Transwell migration assay and wound healing assay were used to verify the capacity of asiaticoside to inhibit MMT. Immunofluorescence assay was performed to observe the subcellular translocation of Nrf2 and expression of HO-1. Results: Asiaticoside inhibited TGF-β1-induced MMT and suppressed Smad signaling in a dose-dependent manner. Migration and invasion activities of HPMCs were decreased by asiaticoside. Asiaticoside decreased TGF-β1-induced ROS, especially in a high dose (150 μM) for 6 h. Furthermore, ML385 partly abolished the inhibitory effect of asiaticoside on MMT, ROS and p-Smad2/3. Conclusions: Asiaticoside inhibited the TGF-β1-induced MMT and ROS via Nrf2 activation, thus protecting the peritoneal membrane and preventing PF.

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Section: Discussionmentioning

confidence: 86%

Asiaticoside inhibits TGF-β1-induced mesothelial-mesenchymal transition and oxidative stress via the Nrf2/HO-1 signaling pathway in the human peritoneal mesothelial cell line HMrSV5

et al. 2020

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“…Further support for this claim came from studies where PPP increased the expression of typical TGF-β target genes, such as connective tissue growth factor (CTGF), in tendinopathic cells [37] and hypertrophic scar dermal fibroblasts [38], considering that the primary effects of TGF-β are at least partially mediated via this growth factor [39]. Similar to CTGF, it is IL11 and NOX4 that are regulated by PPP lysates that mediate the effects of TGF-β on cardiovascular and liver fibrosis [29,30], and acute kidney injury and pulmonary fibrosis [31,34], respectively. Thus, IL11 and NOX4 are not only sensitive TGF-β target genes in vitro as they mediate at least part of the TGF-β activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The impact of heating on the activity of TGF-β is biphasic-TGF-β, because of its binding to latent TGF-β binding proteins, gaining activity by heating [26], while temperatures above 90 • C result in thermal denaturation of TGF-β [27]. Considering that TGF-β is a pleiotropic growth factor that is critically involved in wound healing and bone regeneration [28], and since some of TGF-β effects in vivo are mediated via IL11 [29,30] and NOX4 [31], bioassays based on the expression of these two sensitive target genes are suitable to measure TGF-β activity in PRF.…”

Section: Introductionmentioning

confidence: 99%

Liquid Platelet-Rich Fibrin and Heat-Coagulated Albumin Gel: Bioassays for TGF-β Activity

et al. 2020

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Liquid platelet-rich fibrin (PRF) can be prepared by high centrifugation forces separating the blood into a platelet-poor plasma (PPP) layer and a cell-rich buffy coat layer, termed concentrated PRF (C-PRF). Heating the liquid PPP was recently introduced to prepare an albumin gel (Alb-gel) that is later mixed back with the concentrated liquid C-PRF to generate Alb-PRF. PRF is a rich source of TGF-β activity; however, the overall TGF-β activity in the PPP and the impact of heating the upper plasma layer remains unknown. Here, we investigated for the first time the in vitro TGF-β activity of all fractions of Alb-PRF. We report that exposure of oral fibroblasts with lysates of PPP and the buffy coat layer, but not with heated PPP, provoked a robust increase in the TGF-β target genes interleukin 11 and NADPH oxidase 4 by RT-PCR, and for IL11 by immunoassay. Consistent with the activation of TGF-β signaling, expression changes were blocked in the presence of the TGF-β receptor type I kinase inhibitor SB431542. Immunofluorescence and Western blot further confirmed that lysates of PPP and the buffy coat layer, but not heated PPP, induced the nuclear translocation of Smad2/3 and increased phosphorylation of Smad3. The immunoassay further revealed that PPP and particularly BC are rich in active TGF-β compared to heated PPP. These results strengthen the evidence that not only the cell-rich C-PRF but also PPP comprise a TGF-β activity that is, however, heat sensitive. It thus seems relevant to mix the heated PPP with the buffy coat C-PRF layer to regain TGF-β activity, as proposed during the preparation of Alb-PRF.

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“…Currently, several evidences suggest that NADPH oxidative (Nox) is the dominant source of ROS in the kidney. [26][27][28] Therefore, we analyzed the expression of Nox in NRK-52E cells transfected with shSelT by RNA-seq. As shown in Figure 6A, SelT silencing upregulated the expression of Nox4.…”

Section: Nox1/4 Inhibitor Attenuates Ros Production and Cell Apoptomentioning

confidence: 99%

Selenoprotein T protects against cisplatin‐induced acute kidney injury through suppression of oxidative stress and apoptosis

et al. 2020

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Previously, selenoprotein T (SelT) expression was shown to be induced in nervous, endocrine, and metabolic tissues during ontogenetic and regenerative processes. However, whether SelT plays a critical role in renal diseases remains unclear. Here, we explored the role of SelT in cisplatin‐induced acute kidney injury (AKI). Results revealed that SelT was highly expressed in renal tubules, but its expression was significantly reduced in cisplatin‐induced AKI. Importantly, knocking down of SelT expression in kidney cells in vitro resulted in cisplatin‐induced cell apoptosis, as indicated by the elevation of cleaved‐PARP and Bax expression, Caspase‐3 activity, and number of TUNEL‐positive cells. Moreover, SelT silencing‐induced reactive oxygen species (ROS) production, accompanied by a decrease in intracellular superoxide dismutase (SOD) and catalase (CAT) activity and increase in malondialdehyde (MDA) content. Notably, the protein and mRNA levels of Nox4 were increased in response to SelT downregulation. Furthermore, suppression of Nox4 expression by GKT137831 partially alleviated SelT knockdown‐induced ROS generation and cell apoptosis in cisplatin‐treated kidney cells. Taken together, our findings provide the first evidence that SelT protects against cisplatin‐induced AKI by suppression of oxidative stress and apoptosis.

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TGF-β-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury

Abstract: Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.

Cited by 35 publications

References 46 publications

Asiaticoside inhibits TGF-β1-induced mesothelial-mesenchymal transition and oxidative stress via the Nrf2/HO-1 signaling pathway in the human peritoneal mesothelial cell line HMrSV5

Asiaticoside inhibits TGF-β1-induced mesothelial-mesenchymal transition and oxidative stress via the Nrf2/HO-1 signaling pathway in the human peritoneal mesothelial cell line HMrSV5

Liquid Platelet-Rich Fibrin and Heat-Coagulated Albumin Gel: Bioassays for TGF-β Activity

Selenoprotein T protects against cisplatin‐induced acute kidney injury through suppression of oxidative stress and apoptosis

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