Introduction: Acute kidney injury is characterized by high morbidity and mortality, with renal ischemia/reperfusion (I/R) injury as a critical inducer. Shikonin is the major bioactive compound extracted from the roots of Lithospermum erythrorhizon and possesses diverse pharmacological properties. This study was designed to investigate the biological functions of shikonin in renal I/R injury.
Methods: We established experimental models of renal I/R injury to detect shikonin roles. Renal tissues and blood were collected from mice. Serum levels of creatinine and blood urea nitrogen were evaluated with commercial kits. Kidney damage was detected by measuring KIM-1 protein level and performing hematoxylin and eosin staining and Periodic acid-Schiff staining. Apoptosis in kidney tissues was evaluated by evaluating the expression of apoptosis-related proteins and conducting TUNEL staining. ER stress was determined by measuring ER stress-specific markers. The potential mechanism related to shikonin roles was explored by western blotting and immunofluorescence staining. Cell viability and apoptosis were assayed by CCK-8 and flow cytometry.
Results: For in vivo analysis, renal dysfunctions and tissue structural damage induced by I/R were relieved by shikonin. Additionally, shikonin alleviated ER stress-mediated apoptosis in kidney tissues of I/R mice. Moreover, shikonin activated the SIRT1/Nrf2/HO-1 pathway after I/R, and inhibition of SIRT1 limited the shikonin-mediated protection against ER stress-stimulated apoptosis. For in vitro analysis, shikonin inhibited ER stress-induced apoptosis under H/R conditions. Additionally, inhibition of SIRT1 also attenuated the shikonin-mediated protection against ER stress-induced apoptosis in vitro.
Conclusion: Shikonin can relieve renal I/R injury by activating the SIRT1/Nrf2/HO-1 pathway to inhibit apoptosis caused by ER stress.
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