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Nephropreventive Effect of Shikonin on Murine LPS-induced Septic Acute Kidney Injury via Nrf2 Activation with Antioxidative Responses

Background: The present study explored the nephropreventive effect of shikonin, a naturally occurring herbal medicine, possessing proteasome inhibitory and antioxidant effects via activation of nuclear factorerythroid 2-related factor 2 (Nrf2) against lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) using a murine model.

Methods: Septic AKI was induced in C57BL mice by intraperitoneal administration of LPS (20 mg/kg). Shikonin (5 mg/kg) was administered intraperitoneally to mice 1 hr before the LPS treatment. Development of renal injury, Nrf2 activation and antioxidative responses (heme oxygenase-1; HO-1 and NAD(P)H: quinone oxidoreductase; NQO1) in the kidney of LPS-treated mice with or without shikonin were compared.

Results: Serum levels of Interleukin (IL)-6 and tissue necrotic factor (TNF)-α were markedly elevated in LPStreated mice. However, shikonin administration resulted in a significant decrease in the normally elevated levels of these cytokines. Survival rates of LPS-treated mice and LPS- and shikonin-treated mice were 36 and 82%, respectively. Serum creatinine and blood urea nitrogen (BUN) markedly increased in LPS-treated mice, whereas shikonin improved these renal function markers. Histochemical examination revealed that glomerular and tubular injuries of LPS-treated mice were reduced by shikonin. Serum hydroperoxide and renal malondialdehyde levels were markedly increased by LPS treatment, whereas shikonin significantly suppressed these oxidative stress markers. Shikonin administration induced a marked expression of Nrf2 in the renal nuclear fraction, which was associated with significant increases in mRNA expression of HO-1 and NQO1.

Conclusion: These results suggest that shikonin could be a potential nephropreventive agent against septic AKI, at least in part, through the transient activation of renal Nrf2 followed by induction of its downstream antioxidant molecules.


Madoka Kawara, Rika Matsunaga, Yuko Yamamoto, Go Yoneda, Rika Fujino,Kazuhiko Nishi,Hirofumi Jono and Hideyuki Saito

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