Abstract
Prostaglandin pathway plays multiple roles in various physiological and pathological conditions. The present study aimed to investigate the effect of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in the degradation of prostaglandins, on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice. In this study, male C57BL/6J mice were injected intraperitoneally with LPS (10 mg/kg). SW033291, a potent small-molecule inhibitor of 15-PGDH, was used to investigate the therapeutic potential of 15-PGDH inhibition on LPS-induced AKI. We discovered that the expression of 15-PGDH protein was upregulated in kidneys of LPS-stimulated mice, and it was mainly localized in the cytoplasm of renal tubular epithelial cells in renal cortex and outer medulla. SW033291 administration improved the survival rates of mice and attenuated renal injury of mice that were challenged by LPS. Additionally, inhibition of 15-PGDH also reversed LPS-induced apoptosis of renal cells, increased expression of anti-apoptotic protein Bcl-2, and downregulated expression of Fas, caspase-3, and caspase-8. Pretreatment of SW033291 enhanced autophagy in kidney cells after LPS stimulation. Our data also showed that inhibition of 15-PGDH relieved the level of lipid peroxidation and downregulated NADPH oxidase subunits induced by LPS in mice kidneys but had no significant effect on the release of inflammatory factors, such as IL-6, IL-1β, TNF-α, and MCP-1. Our study demonstrated that inhibition of 15-PGDH could alleviate LPS-induced AKI by regulating the apoptosis, autophagy, and oxidative stress rather than inflammation in mice.
Highlights
MATERIALS AND METHODSAcute kidney injury (AKI) is one of the most common and serious complications of sepsis with a high incidence and mortality rate
For the first time we discovered that the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein was increased in kidneys of LPS-stimulated mice and that it was mainly localized in the cytoplasm of renal tubular epithelial cells in renal cortex and outer medulla
We found that the blockade of 15-PGDH could significantly alleviate the kidney damage and contribute to the survival rate of endotoxemic mice
Summary
Acute kidney injury (AKI) is one of the most common and serious complications of sepsis with a high incidence and mortality rate. For analysis of 15-PGDH expression in LPS-induced AKI, 12 mice were divided into four groups with three mice in each group (n = 3), and each mouse was administered intraperitoneally with 10 mg/kg body weight LPS (from Escherichia coli 0111:B4, SigmaAldrich, St. Louis, MO, United States) for 0, 6, 12, and 24 h, respectively. The other 70 mice were used to explore the role and mechanism of 15PGDH on LPS-induced AKI, as described in the section below. Proteins from the kidney samples of mice were extracted by sonicating the tissues in 1% PMSF-containing RIPA buffer and were centrifuged at 4◦C for 10 min at 12,000 rpm. The PGE2 concentration of the renal tissue homogenate was determined according to the instruction of PGE2 ELISA kit (Huamei Biology Company, Wuhan, China). A value of P < 0.05 was considered to be statistically significant
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