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Abstract

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.


Author(s):

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



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