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High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.

 

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This study aimed to explore the role of necroptosis, an alternative cell death pathway, in the development of diabetic kidney disease (DKD) in diabetes mellitus (DM). The results showed that high glucose levels activate the RIPK1/RIPK3/MLKL signaling pathway, leading to necroptosis and proinflammatory activation in the kidney both in diabetic mice and normal rat kidney tubular cells. The study also found that necroptosis is partly dependent on reactive oxygen species (ROS) and ROS is involved in the necroptosis pathway through a positive feedback loop involving the RIPK1/RIPK3 pathway. Inhibiting the RIPK1/RIPK3/MLKL pathway through the use of necrostatin-1 or N-acetylcysteine was shown to protect the kidney against high glucose-induced damage, decrease proinflammatory cytokine release, and rescue renal function in diabetic mice. The study concluded that high glucose-induced DKD occurs via renal tubular epithelium necroptosis and that inhibiting the RIPK1/RIPK3/MLKL pathway could be a therapeutic target for DKD.

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S1623 Acetylcysteine (N-acetylcysteine) Acetylcysteine (N-acetyl-l-cysteine, NAC,N-acetylcysteine) is a ROS(reactive oxygen species) inhibitor that antagonizes the activity of proteasome inhibitors. It is also a tumor necrosis factor production inhibitor. Acetylcysteine(N-acetyl-l-cysteine) suppresses TNF-induced NF-κB activation through inhibition of IκB kinases. Acetylcysteine(N-acetyl-l-cysteine) induces apoptosis via the mitochondria-dependent pathway. Acetylcysteine(N-acetyl-l-cysteine) inhibits ferroptosis and virus replication.Solutions are unstable and should be fresh-prepared.

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