Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways.

Sepsis, a destructive inflammatory response syndrome, is the principal reason to induce death in the intensive care unit. Loganin has been proved to possess the property of anti-inflammation, antioxidant, neuroprotection, and sedation. The primary aim of this study was to evaluate whether Loganin could alleviate acute kidney injury (AKI) during sepsis and investigate the latent mechanisms. Septic AKI models were established by cecal ligation and puncture (CLP) surgery in mice and given Loganin (20, 40, 80 mg/kg) by gavage. Lipopolysaccharides (LPS)-stimulated human kidney proximal tubular (HK2) cells incubated in Loganin (5, 10, 20 μ M) were used to explore the accurate mechanisms. Survival rate, renal function (creatinine and blood urea nitrogen), and renal pathological changes were detected in septic mice. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), mitochondrial membrane potential, mitochondrial calcium overload, and nuclear factor E2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway activation in vivo and in vitro were determined by commercial kits and Western blot. Cell apoptosis, apoptotic-related protein (cleaved caspase-3, Bcl-2, and Bax) expression and protein kinase B (AKT) phosphorylation in vivo and in vitro were measured by TUNEL staining and Western blot. Finally, AKT blockage by 10 μM LY294002 or Nrf2 inhibition by10 μ M ML385 were utilized to prove the involvement of AKT and Nrf2/HO-1 pathway in AKI during sepsis. We found Loganin treatment (20, 40, 80 mg/kg) mitigated septic AKI reflected by elevated renal function and palliative pathological changes. Oxidative stress and apoptosis in the kidney and LPS-treated HK2 cells were also inhibited by Loganin administration, which was accompanied by AKT and Nrf2/HO-1 pathway activation. Besides, the protective effects of Loganin could be diminished by AKT or Nrf2 blockage, indicating the involvement of AKT and Nrf2/HO-1 pathway. The results suggested that the protective effects of Loganin on AKI during sepsis might be mediated by AKT and Nrf2/HO-1 pathway signaling activation in kidney proximal tubular cells.

Zhang J ，Wang C ，Kang K ，Liu H ，Liu X ，Jia X ，Yu K ... -  《Drug Design Development and Therapy》

Loganin exerts a protective effect on ischemia-reperfusion-induced acute kidney injury by regulating JAK2/STAT3 and Nrf2/HO-1 signaling pathways.

To investigate the role of loganin in hypoxia/reperfusion (H/R)-induced renal tubular epithelial cells and ischemia/reperfusion-induced acute kidney injury (AKI). Cells were received H/R treatment and cultured with different concentrations of loganin. The cell activity and apoptosis were detected. The expressions of apoptosis-related proteins, inflammatory factors, oxidative stress related molecules, and related molecules of JAK2/STAT3 and Nrf2/HO-1 signaling pathways were measured. AKI model of mice was established by I/R procedure, and the kidney was collected for hematoxylin and eosin (HE) staining. H/R treatment inhibited cell activity and apoptosis, but loganin attenuated the effect of H/R. Moreover, loganin inhibited H/R-induced inflammatory response and oxidative stress in tubular epithelial cells. Loganin down-regulated the expression of apoptosis-related proteins, suppressed JAK2/STAT3 pathway, and activated Nrf2/HO-1 pathway. In animal experiment, loganin reduced tubular injury in AKI mice.Loganin had anti-apoptotic, anti-inflammatory, and anti-oxidative stress effects on H/R-induced tubular epithelial cells, and could improve AKI in mice induced by I/R. This effect might be achieved by inhibiting JAK2/STAT3 and activating the Nrf2/HO-1 signaling pathway.

Huang F ，Wang X ，Xiao G ，Xiao J ... -  《-》

Loganin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Response through the Activation of the Nrf2/HO-1 Signaling Pathway in RAW264.7 Macrophages.

Park C ，Lee H ，Kwon CY ，Kim GY ，Jeong JW ，Kim SO ，Choi SH ，Jeong SJ ，Noh JS ，Choi YH ... -  《-》

Dexmedetomidine attenuates ferroptosis by Keap1-Nrf2/HO-1 pathway in LPS-induced acute kidney injury.

Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.

Luo RR ，Yang J ，Sun YL ，Zhou BY ，Zhou SX ，Zhang GX ，Yang AX ... -  《-》

Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice.

Sepsis is defined as end-organ dysfunction resulting from the host's inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown. The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice. The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression. Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression. Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways.

Ren Q ，Guo F ，Tao S ，Huang R ，Ma L ，Fu P ... -  《-》