Interleukin 37 (IL-37) Reduces High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis of Podocytes by Inhibiting the STAT3–Cyclophilin A (CypA) Signaling Pathway

Abstract

Background Diabetic nephropathy (DN), the formation of albuminuria, is one of the most important complications seen in diabetic patients. IL-37, an inhibitor of congenital inflammation and immune response, plays an important role in the occurrence and development of diabetes, but its study in DN has not been previously reported. Material/Methods Podocyte transfection techniques were used to overexpress STAT3 and cyclophilin A (CypA). The expression of IL-37, STAT3, and CypA was detected by RT-qPCR and western blot. Cell survival was detected by CCK-8. The expression of inflammatory factors and molecules related to oxidative stress was detected by ELISA and western blot, and cell apoptosis was detected by flow cytometry and western blot. Results The expression of IL-37 was significantly decreased in high glucose-treated podocytes. IL-37 improved the survival rate of podocytes suffering from high glucose-induced apoptosis. It inhibited the expression of the inflammation-related factors tumor necrosis factor α (TNF-α), IL-1β, IL-6, malondialdehyde (MDA), and lactate dehydrogenase (LDH), and promoted the expression of superoxide dismutase (SOD) in high glucose-treated podocytes. In addition, IL-37 inhibited the expression of the inflammation-related proteins MCP-1, NLRP3, ASC, and caspase-1. IL-37 also inhibited high glucose-induced apoptosis of podocytes by inhibiting the expression of the apoptosis-related proteins Bax and cleaved caspase-3/6/9, and by promoting the expression of Bcl-2. At the same time, we found that the STAT3/CypA signaling pathway was activated after induction by high glucose, while it was inhibited after treatment with IL-37. Overexpression of STAT3 and CypA inhibited the effects of IL-37 on the alleviation of inflammation and oxidative stress and on the reduction of apoptosis of high glucose-treated podocytes. Conclusions IL-37 can significantly reduce podocyte inflammation, oxidative stress, and apoptosis induced by high glucose, and can inhibit the STAT3-CypA signaling pathway. Upregulation of the STAT3-CypA signaling pathway can inhibit the protective effect of IL-37 against podocyte injury induced by high glucose.

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

“…5c ), indicating that CD147 is responsible for CyPA upregulation via JAK pathway. 30

Fig. 5 Spike protein-CD147-CyPA axis contributes to COVID-19 cytokine storm.

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CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 variants

“…4E). Previously, CyPA was reported to be regulated by the JAK-STAT pathway ( 24 ). Indeed, CyPA level could be inhibited by JAK inhibitor (Fig.…”

Current update on theranostic roles of cyclophilin A in kidney diseases

“…Furthermore, a positive correlation has been found between plasma eCyPA level and age, blood sugar level and hemoglobin A1c (HbA1c) level 46 . High glucose also activates signal transducer and activator of transcription 3 (STAT3)-CyPA interaction, which induces inflammation, oxidative stress, and apoptosis in podocytes 47 . IL-37 is an anti - inflammatory and anti - immune response molecule .…”

“…IL-37 is an anti - inflammatory and anti - immune response molecule . A recent study has shown that overexpression of STAT3 and CyPA leads to inhibition of the IL - 37-mediated protective effects against podocyte injury induced by high glucose 47 . These data on kidney cells are consistent with those obtained from human umbilical endothelial cells demonstrating that STAT3 promotes CyPA expression via binding to the STAT3-responsive element (SRE), a specific region in the CyPA gene ( PPIA ) promoter 48 .…”