Tofacitinib Ameliorates Lipopolysaccharide-Induced Acute Kidney Injury by Blocking the JAK-STAT1/STAT3 Signaling Pathway

Abstract

Septic acute kidney injury (AKI) is the most common AKI syndrome in the intensive care unit (ICU), and it accounts for approximately half of AKI cases. Tofacitinib (TOFA) is a pan-Janus kinase (JAK) inhibitor that exhibits potent anti-inflammatory activity in rheumatoid arthritis. However, no study has examined the functional role of TOFA in septic AKI. In the present study, we investigated the protective effects of TOFA on septic AKI and the underlying mechanisms. A lipopolysaccharide- (LPS-) induced AKI model was established in C57BL/6 mice via an intraperitoneal injection of LPS (10 mg/kg). One hour after LPS challenge, the mice were orally administered TOFA (5, 10, or 15 mg/kg) every 6 h until sacrifice at 24 h. We found that TOFA significantly ameliorated LPS-induced renal histopathological changes and dysfunction. TOFA also suppressed the expression levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) and the parameters of oxidative stress (MDA, GSH, SOD, and CAT) in kidney tissues. These results may be associated with the inhibitory effect of TOFA on the JAK-STAT1/STAT3 pathway, which was significantly activated by LPS challenge. TOFA treatment also inhibited LPS-induced activation of the TLR4/NF-κB pathway. In conclusion, we revealed that TOFA had a protective effect on LPS-induced AKI, and it may be a promising therapeutic agent for septic AKI.

Targeting STAT3: A crucial modulator of sepsis

“…and NF-κB pathway activation (Zhu et al, 2020). Tofacitinib also inhibits STAT1 and STAT3 activation in LPS-challenged kidneys, which consequently reduces tubular injury scores, oxidative stress markers, and blood urea nitrogen (BUN) and serum creatinine (Scr) levels (Yun et al, 2021). Besides, many microRNAs are closely associated with the occurrence, development of sepsis AKI.…”

No safe renal warm ischemia time—The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury

“…Signal transducer and activator of transcription 1(STAT1) is a member of STATs, which are important transcription factors that regulate the expression of inflammatory genes ( Leonard and O'Shea, 1998 ). JAK-STAT activation is involved in the pathogenesis of AKI, and is also a key route in the signaling cascade of cytokine mediated AKI ( Yun et al, 2021 ). JAK-STAT inhibitors may prevent and/or treat AKI via blockade of the feedback loop of proinflammatory cytokines, and the inhibition of STAT phosphorylation could also significantly downregulate the production of proinflammatory cytokines during the process of renal inflammation and injury ( Li et al, 2019 ).…”

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

“… 20 , 21 Tofacitinib is a pan-JAK inhibitor that can preferentially inhibit the JAK/STAT1 pathway. 22 , 23 In this study, we explored the effects of tofacitinib on corneal lymphangiogenesis and CGR via the inhibition of M1 macrophage polarization.…”