Lrg1 silencing attenuates ischemia-reperfusion renal injury by regulating autophagy and apoptosis through the TGFß1- Smad1/5 signaling pathway.

BACKGROUND: Dysfunction in the processes of autophagy and apoptosis within renal tubular epithelial cells (RTEc) contributes to renal ischemia-reperfusion injury (IRI). However, the factors influencing this dysfunction remain unclear. Leucine-rich alpha-2-glycoprotein 1 (Lrg1) plays a role in the progression of diabetic nephropathy and kidney fibrosis by modulating the activin receptor-like kinase 1 (ALK1)-Smad1/5/8 and TGF-ß1/Smad3 pathways, respectively. Therefore, we aimed to investigate whether Lrg1 is involved in the pathological mechanisms of renal IRI and whether its effects are related to the dysregulation of autophagy and apoptosis in RTEc. METHODS: We conducted in vitro and in vivo experiments using CoCl2-induced hypoxic human kidney-2 (HK-2) cells and mice with renal IRI, respectively. Lrg1 was silenced using siRNA and lentiviral vectors in HK-2 cells and mouse kidneys. Rapamycin (Rapa) and methyladenine were applied to regulate autophagy in renal IRI models. RESULTS: Increased Lrg1 expression was observed in hypoxic HK-2 cells and in the kidneys of mice with renal IRI. Silencing of Lrg1 through siRNA and lentiviral approaches restored autophagy and suppressed apoptosis in CoCl2-induced hypoxic HK-2 cells and renal IRI models. Additionally, reduced Lrg1 expression alleviated kidney damage caused by renal IRI. The downregulation of Lrg1 expression restrained the TGFß-Smad1/5 signaling pathway in hypoxic-induced HK-2 cells and renal IRI by reducing ALK1 expression. Lastly, the enhancement of autophagy, achieved through Rapa treatment, provided protection against renal IRI in mice. CONCLUSIONS: Our findings suggest that Lrg1 silencing can be applied as a potential therapeutic target to inhibit the TGFß1-Smad1/5 pathway, thereby enhancing autophagy and decreasing apoptosis in patients with acute kidney injury.

Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) are beneficial antibacterial defense structures. However, excessive NETs have also been linked to tissue damage and organ dysfunction. LPS and Gram-negative bacteria induce the formation of reactive oxygen species (ROS)-dependent NETs via the JNK pathway. It was found previously that knockdown of nicotinamide phosphoribosyltransferase (NAMPT) upregulates surfactant protein B (SFTPB or SP-B) and attenuates LPS-induced acute lung injury (ALI) via inhibiting JNK activation. This study investigated the effect of FK866, an intracellular NAMPT inhibitor, on the formation of LPS-induced NETs in mouse bronchoalveolar lavage (BAL) neutrophils and in differentiated HL-60 cells. The results show that inhibition of NAMPT by FK866 suppresses NETs formation in BAL neutrophils from the mice exposed to LPS. FK866 also suppresses NETs formation in the differentiated HL-60 cells stimulated with LPS. Additional data indicate that these effects are mediated by suppressing ROS production at least partly via inhibiting JNK activation and depleting NAD(P)H. The utility of inhibition of intracellular NAMPT may be a potential therapy for LPS-induced NETs-related diseases.

Neonatal neuron specific enolase, a sensitive biochemical marker of neuronal damage, is increased in preeclampsia: A retrospective cohort study.

BACKGROUND: Preeclampsia leads to chronic intrauterine hypoxia by interfering with placental blood supply. We aimed to investigate whether preeclampsia exposure has an influence on central nervous system of infants, as evaluated by analyzing neonatal serum neuron specific enolase (NSE). METHODS: This was a retrospective study including infants born in Nanfang hospital between Jan 2018 and Feb 2019 without asphyxia. They were divided into normotensive control group and preeclampsia group to compare the NSE levels. Furthermore, PE group was divided into five subgroups by lipstick of urine protein from 0 to 4+ to examine the relationship between urine protein and neonatal NSE. RESULTS: Of the 86 selected neonates, there were 40 in control group and 46 in preeclampsia group. The NSE levels were significantly higher in infants with preeclampsia exposure compared to those infants in control group (45.504 ± 17.926 vs 30.690 ± 4.475, P < 0.0001). Multiple regression analyses revealed that the preeclampsia (ß coef = 0.394, p = 0.041), 4+ proteinuria (ß coef = 0.558, p < 0.0001) and 3+ proteinuria (ß coef = 0.356, p = 0.005) were significant independent variables predicting elevated serum NSE concentration. CONCLUSION: For the first time, this research has suggested the increase of neonatal NSE in preeclampsia, and the quantity of maternal proteinuria may be able to predict neonatal NSE elevation. Long-term neurodevelopmental follow-up and targeted preventive strategies are advised for this underrecognized high-risk population.