Inhibiting USP11 attenuates sepsis-associated acute kidney injury by downregulating TGFBR2/Smad3 signaling

Lu Wang¹Wen Tang¹Long Jiang¹Daquan Zhang¹Zhigao Wang¹Rennan Guo¹Jingjing Wang¹Dong Xiao^2*

• ¹People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, China
• ²People's Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China

Sepsis-associated acute kidney injury (AKI) is a common complication of sepsis, a severe inflammatory disease with high mortality. The TGF-β/Smad signaling pathway plays important roles in the progression of sepsis, and targeting TGF-β receptor II (TGFBR2) has been shown to ameliorate its effects. Ubiquitin-specific peptidase 11 (USP11) stabilizes TGFBR2 and enhances TGF-β/Smad signaling pathway. In this study, we evaluated the effects of USP11 inhibition on sepsis-associated AKI. A septic mouse model was established and treated with USP11 inhibitor Mitoxantrone. The expression of TGFBR2, phosphorylation of Smad3, and levels of kidney injury markers, inflammatory cytokines, and oxidative stress markers were measured in kidney tissues. Elevated expression of TGFBR2 and phosphorylated Smad3 was detected in the kidneys of septic mice. Mitoxantrone treatment reduced the expression of TGFBR2 and suppressed the activation of Smad3. It also attenuated kidney injury, and reduced inflammation and oxidative stress in the kidneys of septic mice. USP11 inhibition by Mitoxantrone ameliorated sepsis-associated AKI by downregulating TGFBR2/Smad3 signaling.