Dexmedetomidine ameliorates lipopolysaccharide‐induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK‐3β/Nrf2 signaling pathway

Abstract

Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there are currently no effective therapies. Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)‐induced AKI. Dexmedetomidine (DEX) has been reported to have remarkable anti‐inflammatory and antioxidant effects. Here, we examined the renoprotective effects of DEX and potential underlying mechanisms in rats with LPS‐induced AKI. We analyzed renal function and structure; serum inflammatory cytokine; renal oxidant and antioxidant levels; and renal expression of glycogen synthase kinase‐3β (GSK‐3β)/nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway‐related proteins in rats 4 hr after administration of LPS. Pretreatment with DEX improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. Treatment with DEX and the GSK‐3β inhibitor SB216367 promoted phosphorylation of GSK‐3β, induced Nrf2 nuclear translocation, and increased transcription of the Nrf2 target genes heme oxygenase‐1 and NAD(P)H quinone oxidoreductase‐1, primarily in renal tubules. Alpha‐2‐adrenergic receptor (α2‐AR) antagonist atipamezole and imidazoline I 2 receptor (I 2R) antagonist idazoxan reversed the effects of DEX. These results suggest that the renoprotective effects of DEX are mediated via α2‐AR and I 2R‐dependent pathways that reduce inflammation and oxidative stress through GSK‐3β/Nrf2 signaling.

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

“…We have confirmed that DEX protects against LPS-induced AKI via anti-inflammatory and anti-oxidative mechanisms (Chen et al, 2019;Feng et al, 2019;Yao et al, 2019). Also, we found that DEX regulated renal autophagy, a phenomenon that was accompanied by the amelioration of oxidative stress and cell apoptosis.…”

“…LPS, a known toxic component of Gram-negative bacteria, is widely used to induce SAKI in animal models (Jou-Valencia et al, 2018), and studies have confirmed that the intraperitoneal administration of LPS for 4 h induces AKI (Chen et al, 2019;Feng et al, 2019). After LPS treatment, the indicators of kidney injury (BUN, Cre, KIM-1, and NGAL) are significantly increased, suggesting renal dysfunction and kidney injury.…”

“…The kidney is one of the most vulnerable organs during sepsis, and acute kidney injury (AKI) occurs in 40-50% of septic patients with a mortality rate of up to 60% (Plotnikov et al, 2019). The underlying pathogenesis of sepsis acute kidney injury (SAKI) is not well understood but includes oxidative stress (Chen et al, 2019), inflammation (Feng et al, 2019), and apoptosis (Kang et al, 2018). Recently, it was reported that autophagy played a key role in SAKI, and the inhibition of autophagy resulted in the development of AKI during sepsis (Ho et al, 2016).…”

“…Dexmedetomidine (DEX) is a highly selective alpha-2 adrenergic receptor (a 2 -AR) agonist (Kawazoe et al, 2017). Our previous studies have shown that DEX exhibits anti-inflammatory and anti-oxidative effects in LPS-induced AKI (Chen et al, 2019;Feng et al, 2019;Yao et al, 2019). It has also demonstrated that DEX has anti-inflammatory and anti-apoptotic effects in LPS-induced AKI (Kang et al, 2018).…”

Roles of Nrf2 in Protecting the Kidney from Oxidative Damage

“…Basic studies of the Nrf2 pathway have demonstrated multiple cytoprotective functions of Nrf2 and unveiled regulatory mechanisms of Nrf2 activity in response to oxidative stress. Recent studies have shown that activated Nrf2 in nuclei is degraded through βTrCP-mediated ubiquitination to avoid overactivation of Nrf2 [90,99,120], supporting the safety of chemical compounds activating Nrf2 for patients. Because oxidative stress is a primary factor for tissue damage in every organ, pharmacologically driving the antioxidative response system by Nrf2 activators is plausible for curing a variety of diseases.…”