resolvin-d1 and Acute-Kidney-Injury

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1

Topics: Acute Kidney Injury; Albumins; Animals; Aspirin; Biomarkers; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Female; Inflammation; Kidney Function Tests; Kidney Glomerulus; Male; Mice; Mice, Inbred BALB C; Proteinuria; RNA, Messenger; Sepsis

To investigate the effects of aspirin-triggered resolvin D1 (AT-RvD1) on paraquat-induced acute renal injury (ARI) in mice.. The ARI mouse model was established by administering 28 mg/kg paraquat to C57BL/6J mice by intraperitoneal injection. The mice received 10 or 100 ng AT-RvD1 by intravenous injection in the tail vein 2 h after toxication. The mice were euthanized 6, 24, or 72 h post-paraquat injection to collect blood and renal tissues. The samples were used to evaluate the pathological changes, renal function, inflammation and oxidative stress in the renal tissues.. Compared with those of the PQ group, AT-RvD1 administration mitigated the pathological changes and improved renal function, activated Nrf2 and upregulated the expression of its downstream antioxidant genes (NQO1, HO-1, SOD1 and GPx1), and decreased the MDA and protein carbonyls content in renal tissues. Treatment also reduced the expression of P-selectin in renal tissues, the percentage of Ly-6G. The administration of AT-RvD1 can effectively suppress paraquat-induced oxidative stress injury and the inflammatory reaction, and alleviate paraquat-induced ARI.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Cytokines; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Gene Expression Regulation; Herbicides; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Neutrophils; Oxidative Stress; Paraquat

Resolvin D1 (RvD1) is a newly found anti-inflammatory bioactive compound derived from polyunsaturated fatty acids. The current study aimed to explore the protective effect of RvD1 on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its possible mechanism.. Both in vivo and in vitro studies were conducted. Male BALB/c mice were randomly divided into control group (saline), LPS group (LPS 5 mg/kg), RvD1 group (RvD1 5 μg/kg + LPS 5 mg/kg), and blockage group (Boc-MLP 5 μg/kg + RvD1 5 μg/kg + LPS 5 mg/kg). Boc-MLP is a RvD1 receptor blocker. The mice were intraperitoneally injected with these drugs and recorded for general condition for 48 h, while the blood and kidneys were harvested at 2, 6, 12, 24, and 48 h time points, respectively (n = 6 in each group at each time point). Human proximal tubule epithelial cells (HK-2) were randomly divided into control group (medium only), LPS group (LPS 5 μg/ml), RvD1 group (RvD1 10 ng/ml + LPS 5 μg/ml), and blockage group (Boc-MLP 10 ng/ml + RvD1 10 ng/ml + LPS 5 μg/ml). The cells were harvested for RNA at 2, 4, 6, 12, and 24 h time points, respectively (n = 6 in each group at each time point). Blood creatinine was tested by using an Abbott i-STAT portable blood gas analyzer. Tumor necrosis factor-α (TNF-α) level was detected by ELISA. Kidney pathology was observed under hematoxylin and eosin (HE) staining and transmission electron microscope (TEM). We hired immune-histological staining, Western blotting, and fluorescence quantitative polymerase chain reaction to detect the expression of RvD1 receptor ALX, nuclear factor-kappa B (NF-κB) signaling pathway as well as caspase-3. Kidney apoptosis was evaluated by TUNEL staining.. RvD1 receptor ALX was detected on renal tubular epithelials. Kaplan-Meier analysis indicated that RvD1 improved 48 h animal survival (80%) compared with LPS group (40%) and RvD1 blockage group (60%), while RvD1 also ameliorated kidney pathological injury in HE staining and TEM scan. After LPS stimulation, the mRNA expression of toll-like receptor 4, myeloid differentiation factor 88, and TNF-α in both mice kidneys and HK-2 cells were all up-regulated, while RvD1 substantially inhibited the up-regulation of these genes. Western blotting showed that the phosphorylated-IκB/IκB ratio in LPS group was significantly higher than that in the control group, which was inhibited in the RvD1 group. RvD1 could inhibit the up-regulation of cleaved-caspase-3 protein stimulated by LPS, which was prohibited in RvD1 blockage group. RvD1 group also had a lower proportion of apoptotic nuclei in mice kidney by TUNEL staining compared with LPS group.. In LPS-induced AKI, RvD1 could decrease TNF-α level, ameliorate kidney pathological injury, protect kidney function, and improve animal survival by down-regulating NF-κB inflammatory signal as well as inhibiting renal cell apoptosis.

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Docosahexaenoic Acids; Down-Regulation; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Tumor Necrosis Factor-alpha

The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Blood Urea Nitrogen; Claudin-4; Creatinine; Cytoprotection; Disease Models, Animal; Docosahexaenoic Acids; Endotoxins; Extracellular Signal-Regulated MAP Kinases; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Kidney; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Time Factors; Vascular Cell Adhesion Molecule-1