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

Abstract

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 factor-erythroid 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 tumor necrosis 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.

Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling

“…Shikonin (SHK) is a natural product extracted from the roots of Lithospermum erythrorhizon [8]. Recent studies have shown that SHK can prevent septic acute kidney injury in mice induced by LPS via Nrf2 activation [9] and inhibit oxidized LDL-induced monocyte adhesion via up-regulation of Nrf2-mediated antioxidation in EA. hy926 endothelial cells [10].…”

Gromwell (Lithospermum erythrorhizon) root extract protects against glycation and related inflammatory and oxidative stress while offering UV absorption capability

“…Activation of the Nrf2 pathway and glutathione synthesis prior to glycation promotes detoxification of glycation‐related carbonyls . Antioxidant benefits of shikonin have been described, including activation of the Nrf2/ARE pathway . We have shown GR extract possesses similar activation of the Nrf2/ARE pathway, comparable to the known Nrf2/ARE inducer, sulforaphane .…”

LBP reduces theinflammatory injuryof kidney in septic rat and regulates the Keap1-Nrf2∕ARE signaling pathway

“…LBP has been shown efficient in diabetic kidney disease models; diabetic rats treated with LBP (10 mg/kg) for 8 weeks showed increased activity of antioxidant enzymes and increased scavenging of oxygen radicals 14 . Recently, Kawara et al reported that oxidative damage caused by LPS induced AKI may be regulated through the Nrf2 signal pathway 10 . Nrf2 is a nuclear transcription factor which is related to oxidative stress reaction and plays an important role in cell defense and protection.…”

“…Also, it has been demonstrated that LBPs exhibit anti-aging and neuroprotective functions both in vitro and in vivo 5 , 6 In addition, as a potent antioxidant, LBPs have been shown to up-regulate the level of antioxidant biomarkers in human serum 7 and protect the body from chemical/exercise-induced oxidative stress 8 , 9 . Recently, Kawara et al 10 . reported that shikonin a major component of zicao (a Chinese herbal medicine with various biological activities) possesses antioxidant effects via activation of Nrf2 against lipopolysaccharide (LPS)-induced AKI in a murine model.…”