Inhibition ofUSP15ameliorates high‐glucose‐induced oxidative stress and inflammatory injury in podocytes through regulation of theKeap1/Nrf2signaling

Abstract

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 HGinduced injury by enhancing Nrf2 activation via Keap1.

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

“…In agreement with this, USP15 deficiency also increased nuclear Nrf2 levels in conjunction with HOX1 and NQO1 expression [ 150 ]. Mechanistically, USP15 retains Nrf2 in the cytoplasm, stabilizing Keap1, an inhibitor of the nuclear translocation of Nrf2 [ 43 , 150 ].…”

“…As with USP14, USP15 was also increased in podocytes following high glucose treatment [ 150 ]. Knockdown of Usp15 mitigated apoptosis, oxidative stress, and NF-κB-dependent induction of proinflammatory cytokines elicited by high glucose treatment [ 150 ].…”

“…As with USP14, USP15 was also increased in podocytes following high glucose treatment [ 150 ]. Knockdown of Usp15 mitigated apoptosis, oxidative stress, and NF-κB-dependent induction of proinflammatory cytokines elicited by high glucose treatment [ 150 ]. In agreement with this, USP15 deficiency also increased nuclear Nrf2 levels in conjunction with HOX1 and NQO1 expression [ 150 ].…”

“…Knockdown of Usp15 mitigated apoptosis, oxidative stress, and NF-κB-dependent induction of proinflammatory cytokines elicited by high glucose treatment [ 150 ]. In agreement with this, USP15 deficiency also increased nuclear Nrf2 levels in conjunction with HOX1 and NQO1 expression [ 150 ]. Mechanistically, USP15 retains Nrf2 in the cytoplasm, stabilizing Keap1, an inhibitor of the nuclear translocation of Nrf2 [ 43 , 150 ].…”

“…It is presently not possible to create a progress chart of NAFLD, including all USPs listed above. Similarly, independent studies identified USP36 in renal epithelial cells, and USP14, 15, and 22 in podocytes as complicating factors for diabetic nephropathy; however, the contribution of each USP to disease etiology is still unclear [ 138 , 144 , 147 , 150 ]. Combinatorial KOs of several USPs and the concomitant transduction of USPs might clarify the role of each USP in metabolic disorders and downstream molecular events.…”