Abstract
Objective At present, renal injury caused by sepsis seriously endangers the health of patients. Our paper proposed to study the protective effects of meloxicam (Mel) in sepsis-induced acute kidney injury (SAKI) and the underlying mechanisms. Methods The in vitro and in vivo models of SAKI were established using lipopolysaccharide (LPS). Mel was injected intraperitoneally at 60 mg/kg into male C57BL/6 mice 4 hours before LPS injection (10 mg/kg). The HK-2 cells were treated with LPS (1 μg/mL) and Mel (40 μM). The renal function and renal pathological changes as well as renal inflammation and apoptosis were detected in SAKI mice. The inflammation and apoptosis of HK-2 cells induced by LPS were also detected. Results The treatment of Mel significantly decreased the elevated levels of serum creatinine (Scr) and blood urea nitrogen (BUN) in SAKI mice. In addition, the results of HE staining suggested that Mel significantly reduced kidney damage in SAKI mice. Consistently, Mel reduced the expression of LPS-induced kidney injury markers (NGAL and KIM-1). Moreover, LPS induced the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the kidney, which can be reduced by Mel. Furthermore, Mel effectively reduced the number of apoptotic cells and inhibited the expression of proapoptotic-related proteins (cleaved Caspase-3 and Bax) but increased the antiapoptotic-related protein (Bcl-2) in the kidneys of SAKI mice. Mechanistically, Mel inhibited the phosphorylation of P65 but induced the phosphorylation of AKT and the expression of glycoprotein B of nonmetastatic melanoma (GPNMB). However, knocking down GPNMB can eliminate the anti-inflammatory and antiapoptotic effects of Mel. Conclusion Mel alleviated sepsis-induced kidney injury by inhibiting kidney inflammation and apoptosis via upregulating GPNMB.
Highlights
Sepsis is a severe, uncontrolled, systemic inflammatory response syndrome caused by various pathogen infections, trauma, burns, and so on, which can cause septic shock and multiorgan dysfunction syndrome
cyclooxygenase 2 (COX2) is induced to increase in the early stages of inflammation, which is triggered by various factors such as endotoxins, growth factors, and proinflammatory cytokines [4, 5]
LPS damaged the renal function of mice, which was manifested by the increase of serum creatinine (Scr) and blood urea nitrogen (BUN), while the renal function of mice pretreated with Mel was significantly improved compared with mice in the LPS group (Figures 1(a) and 1(b))
Summary
Sepsis is a severe, uncontrolled, systemic inflammatory response syndrome caused by various pathogen infections, trauma, burns, and so on, which can cause septic shock and multiorgan dysfunction syndrome. The kidney is one of the most vulnerable target organs for sepsis. Despite the use of antibiotics or immunomodulatory therapeutic applications, it is still unable to effectively control multiple organ dysfunction and death in patients. A large number of studies have shown that SAKI is a complex pathological process caused by multiple factors, involving various molecular mechanisms such as oxygen-free radical damage, inflammation and apoptosis, endoplasmic reticulum stress, and microvascular dysfunction. A selective cyclooxygenase 2 (COX2) inhibitor, is a new type of nonsteroidal anti-inflammatory drug (NSAID) with low side effects and a long half-life for the treatment of rheumatoid arthritis and osteoarthritis [1–3].
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