MIF inhibitor ISO-1 alleviates severe acute pancreatitis-associated acute kidney injury by suppressing the NLRP3 inflammasome signaling pathway

Background: Acute kidney injury (AKI) is an important complication of severe acute pancreatitis (SAP) with a poor prognosis. The methyl ester of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage migration inhibitory factor (MIF), has protective effects against many diseases. Our previous study confirmed MIF inhibition alleviated SAP. Here, we explored the effects of ISO-1 in an experimental mouse model of SAP-associated AKI induced by l-arginine.

Methods: Mice were randomly divided into four treatment groups (n = 6 each): control (CON), SAP, SAP + ISO-1, and ISO-1. Histopathologic examination was used to observe damage in pancreatic and renal tissues. Biochemical and enzyme-linked immunosorbent assays (ELISA) kits were used to measure the serologic indicators amylase, Lipase, creatinine, uric acid, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Immunohistochemistry was used to detect protein expression of NLRP3, ASC and Caspase-1, and the infiltration of myeloperoxidase (MPO)-positive neutrophils in kidney tissue. Western blotting was used to detect NLRP3, ASC and Caspase-1 and IL-1β protein expression, and Real-Time PCR was used to measure MIF, IL-6, TNF-α, IL-1β and IL-18 mRNA levels in kidney tissue.

Results: ISO-1 treatment alleviated pathological damage in pancreatic and renal tissues, and reduced the serum levels of amylase, Lipase, creatinine, uric acid, IL-6 and TNF-α. ISO-1 also reduced protein expression of NLRP3, ASC, Caspase-1 and IL-1β, mRNA expression of MIF, IL-6, TNF-α, IL-1β and IL-18, and the infiltration of MPO-positive neutrophils in kidney tissue.

Conclusion: ISO-1 has a protective effect against experimental SAP-associated AKI. And the mechanism may be associated with ISO-1 inhibiting NLRP3 inflammasome signaling pathway.