Inhibition of USP15 ameliorates high-glucose-induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling.

Erdi Xu, Chunyan Yin, Xiaoqing Yi, Yuesheng Liu

Environmental toxicology 2022 Apr

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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. © 2021 Wiley Periodicals LLC.

Citation

Erdi Xu, Chunyan Yin, Xiaoqing Yi, Yuesheng Liu. Inhibition of USP15 ameliorates high-glucose-induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling. Environmental toxicology. 2022 Apr;37(4):765-775