Abstract
Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-β, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.
Highlights
Acute kidney injury (AKI) is a severe clinical syndrome that rapidly causes renal dysfunction and contributes to a high mortality rate (Bellomo et al, 2012)
Renal function was measured to investigate the protective effect of ibudilast on Folic acid (FA)-induced AKI, and the FA injection induced dramatic increase in serum creatinine and BUN levels to 91.1 ± 3.16 μmol/L and 13.9 ± 0.70 mmol/L, respectively, indicating impaired renal function (Figures 1A,B)
Tubular injuries were assessed by quantification of hematoxylin and eosin (HE)-stained sections and revealed significantly increased tubulointerstitial injury scores (3.0 ± 0.22) in mice injected with FA injection, which were reduced by ibudilast administration (0.8 ± 0.20; Figure 1E)
Summary
Acute kidney injury (AKI) is a severe clinical syndrome that rapidly causes renal dysfunction and contributes to a high mortality rate (Bellomo et al, 2012). Pyroptosis is characterized by caspase-1 dependence, the formation of pores in the plasma membrane, cell swelling, and cytolysis, leading to DNA fragmentation and the release of inflammatory factors (Wu et al, 2016). Many studies have reported that pyroptosis of tubular epithelial cells contributes to tubular necrosis and inflammation, which enhance kidney damage (Chung et al, 2012; Krautwald and Linkermann 2014; Lorenz et al, 2014)
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