Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways
November
Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways
Jian-bo Yu 0 1
Jia Shi☯ 0 1
Yuan Zhang☯ 0 1
Li-rong Gong 0 1
Shu-an Dong 0 1
Xin-shun Cao 0 1
Li-li Wu 0 1
Li-na Wu 0 1
0 Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University , Tianjin , China
1 Editor: Benedetta Bussolati , Center for Molecular Biotechnology, ITALY
Electroacupuncture at select acupoints have been verified to protect against organ dysfunctions during endotoxic shock. And, heme oxygenase (HO)-1 as a phase II enzyme and antioxidant contributed to the protection of kidney in septic shock rats. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway mediated the activation of NF-E2 related factor-2 (Nrf2), which was involved in HO-1 induction. To understand the efficacy of electroacupuncture stimulation in ameliorating acute kidney injury (AKI) through the PI3K/Akt/Nrf2 pathway and subsequent HO-1 upregulation, a dose of LPS 5mg/kg was administered intravenously to replicate the rabbit model of AKI induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Neiguan acupoints for five consecutive days while sham electroacupuncture at non-acupoints as control. Results displayed that electroacupuncture stimulation significantly alleviated the morphologic renal damage, attenuated renal tubular apoptosis, suppressed the elevated biochemical indicators of AKI caused by LPS, enhanced the expressions of phospho-Akt, HO-1protein, Nrf2 total and nucleoprotein, and highlighted the proportions of Nrf2 nucleoprotein as a parallel. Furthermore, partial protective effects of elecroacupuncture were counteracted by preconditioning with wortmannin (the selective PI3K inhibitor), indicating a direct involvement of PI3K/Akt pathway. Inconsistently, wortmannin pretreatment made little difference to the expressions of HO-1, Nrf2 nucleoprotein and total protein, which indicated that PI3K/Akt may be not the only pathway responsible for electroacupuncture-afforded protection against LPS-induced AKI. These findings provide new insights into the potential future clinical applications of electroacupuncture for AKI induced by endotoxic shock instead of traditional remedies.
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Funding: Financial support for this research was
provided by grant No. 81372096 from the National
Natural Science Foundation of China, Beijing, China,
and grant No. 12ZCZDSY013300 from the Key
Projects in the Tianjin Science & Technology Pillar
Program, Tianjin, China. The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
Septic shock is the most common contributing factor to acute kidney injury (AKI) in critically
patients, and even progress into acute renal failure [1]. The combination of acute renal failure
and sepsis accounts for more than 70% mortality, despite multifarious potential interventions
[2]. Lipopolysacchride (LPS) is a primary initiator of inflammatory and hemodynamic
perturbations of sepsis and involved in experimental AKI studies [3]. There is experimental evidence
that endotoxin-related increase in tumor necrosis factor-α (TNF-α) and oxygen radicals are
major causes of AKI during endotoxic shock [4, 5]. Heme oxygenase (HO)-1, as the rate
limiting enzyme of heme degradation, was first recognized in preserving renal function and
reducing mortality [6]. Our prior studies definitely elucidated the protective role of HO-1 on the
kidney in endotoxic shock rats [7]. The biological effect of HO-1 attributed to the degradation
of heme and the products of enzymatic reaction including biliverdin and carbon monoxide,
which exerted antioxidant, antiproliferative and also anti-inflammatory properties [8].
Acupuncture represents a potentially valuable adjunct to prevent clinical disorders in China
and other Asian countries for the past 3000 years [9]. It was proven that electrical stimulation
of the vagus nerve could modulate systemic inflammatory responses to endotoxin, inhibit the
synthesis of TNF and prevent the development of shock [10]. In addition, electroacupuncture
was found to produce neuro-protective effect by enhancing the activities of antioxidant
enzymes and reducing the extent of lipid peroxidation [11]. Traditionally, Zusanli (ST36) and
Neiguan (PC6), two specific points, were considered of choice for good health care. Recent
studies have shown that ST36 acupuncture pretreatment exerted protective effects against
sepsis-induced kidney injury [12]. Besides, Liu et al indicated that electroacupuncture at PC6
retrieved blood pressure and improved endotoxic shock in rats [13]. However, little was known
about its mechanisms of modulation.
Several transcriptional factors including NF-E2 related factor-2(Nrf2), activator protein
(AP)-1 and nuclear factor-κβ (NF-κβ (...truncated)