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Inhibition of USP15 ameliorates high‐glucose‐induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling
Ubiquitin‐specific peptidase 15 (USP15) is implicated in the pathogenesis of numerous diseases. However, whether USP15 plays a role in diabetic nephropathy remains undetermined. This project was designed to determine the potential role of USP15 in mediating high glucose (HG)‐induced podocyte injury, a key event in the pathogenesis of diabetic nephropathy. We found that USP15 levels were elevated in podocytes after HG stimulation. Inhibition of USP15 led to decreases in HG‐evoked apoptosis, oxidative stress, and inflammation in podocytes. Further investigation showed that inhibition of USP15 enhanced the activation of NF‐E2‐related factor 2 (Nrf2) and expression of Nrf2 target genes in HG‐simulated podocytes. Moreover, depletion of Kelch‐like ECH‐associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation. In addition, Nrf2 suppression reversed USP15‐inhibition‐induced protective effects in HG‐injured podocytes. Taken together, these data indicate that USP15 inhibition protects podocytes from HG‐induced injury by enhancing Nrf2 activation via Keap1.
Inhibition of USP15 ameliorates high‐glucose‐induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling
Ubiquitin‐specific peptidase 15 (USP15) is implicated in the pathogenesis of numerous diseases. However, whether USP15 plays a role in diabetic nephropathy remains undetermined. This project was designed to determine the potential role of USP15 in mediating high glucose (HG)‐induced podocyte injury, a key event in the pathogenesis of diabetic nephropathy. We found that USP15 levels were elevated in podocytes after HG stimulation. Inhibition of USP15 led to decreases in HG‐evoked apoptosis, oxidative stress, and inflammation in podocytes. Further investigation showed that inhibition of USP15 enhanced the activation of NF‐E2‐related factor 2 (Nrf2) and expression of Nrf2 target genes in HG‐simulated podocytes. Moreover, depletion of Kelch‐like ECH‐associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation. In addition, Nrf2 suppression reversed USP15‐inhibition‐induced protective effects in HG‐injured podocytes. Taken together, these data indicate that USP15 inhibition protects podocytes from HG‐induced injury by enhancing Nrf2 activation via Keap1.
Inhibition of USP15 ameliorates high‐glucose‐induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling
Xu, Erdi (Autor:in) / Yin, Chunyan (Autor:in) / Yi, Xiaoqing (Autor:in) / Liu, Yuesheng (Autor:in)
Environmental Toxicology ; 37 ; 765-775
01.04.2022
11 pages
Aufsatz (Zeitschrift)
Elektronische Ressource
Englisch
Keap1 , Nrf2 , high glucose , USP15 , diabetic nephropathy
| Wiley | 2024