Abstract. Nephrotic syndrome (NS) is the most common kidney disease in clinical practice and may lead to end-stage renal failure. Astragalosides (AST) have been clinically tested for the treatment of NS, but their mechanism of action has remained to be elucidated. The aim of the present study was to investigate the effect of AST on the structure and function of podocytes with adriamycin (ADR)-induced damage and to elucidate the underlying molecular mechanisms. The mouse podocyte clone 5 (MPC5) immortalized mouse podocyte cell line was treated with 0.5 µmol/l ADR to establish a podocyte injury model. The MPC5 podocytes were divided into a control group, a podocyte injury group and a low-, medium-and high-concentration AST treatment group. The results indicated that the survival rate of the podocyte injury group was significantly decreased compared with that in the control group and each AST-treated group had an increased survival rate compared with that in the podocyte injury group. Furthermore, each dose of AST significantly inhibited the ADR-associated increases the levels of lactate dehydrogenase and malondialdehyde and the decrease in the activity of superoxide dismutase in MPC5 podocytes. In addition, AST improved the migration ability of MPC5 podocytes and suppressed the cytoskeletal rearrangement associated with ADR-induced damage. Furthermore, matrix metalloproteinase (MMP)-2 and -9 were decreased in the podocyte injury group, which was inhibited by different concentrations of AST. Thus, AST was able to maintain the balance of oxidative stress in podocytes cultured with ADR and protect them from ADR-induced injury. The mechanism may be associated with the upregulation of MMPs.
Background It is unclear why primary nephrotic syndrome (PNS) patients often have dyslipidemia. Recent studies have shown that angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism. In this study, we explored how ANGPTL3 impacts dyslipidemia during PNS development. Methods We measured the serum levels of ANGPTL3 in PNS patients (n=196). Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different ages. Moreover, in this study, we used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to investigate lipopolysaccharide (LPS)-induced nephrosis. Results Compared with that in the healthy group, the serum level of ANGPTL3 in the PNS group was significantly increased (32 (26.35-39.66) ng/ml vs. 70.44 (63.95-76.51) ng/ml, Z =-4.81, P < 0.001). There were significant correlations between the serum level of ANGPTL3 and the levels of cholesterol (r=0.34, P < 0.001), triglycerides (r= 0.25, P = 0.001) and low-density lipoprotein (r= 0.50, P < 0.001) in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features of angptl3-tg mice included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement. Compared to wild-type mice, angptl3-/- mice showed significantly lower degrees of lipid dysfunction and proteinuria after stimulation with LPS. The effects of ANGPTL3 on nephrotic dyslipidemia were confirmed in cultured hepatocytes subjected to angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) levels were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS. Conclusions ANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, during PNS pathogenesis. Inhibition of LPL expression may the mechanism by which ANGPTL3 induces hyperlipidemia in PNS.
Background This study aimed to investigate the expression characteristics of ANGPTL8 in patients with primary nephrotic syndrome and its possible correlation with hyperlipidemia and proteinuria. Methods ANGPTL8 levels were determined using an enzyme-linked immunosorbent assay in 133 subjects with PNS and 60 healthy controls. Results Compared with healthy controls, subjects with primary nephrotic syndrome had higher levels of serum and urine ANGPTL8 (P < 0.001). In primary nephrotic syndrome patients, serum ANGPTL8 was positively correlated with cholesterol (r = 0.209, P < 0.05) and triglycerides (r = 0.412, P < 0.001), while there was no correlation with 24 hUTP. Urine ANGPTL8 was positively correlated with high-density lipoprotein cholesterol (r = 0.181, P < 0.05) and was significantly negatively correlated with creatinine (r = − 0.323, P < 0.001), eGFR (r = − 0, P < 0.001) and 24 hUTP (r = − 0.268, P = 0.002). Interestingly, the urine ANGPTL8 concentrations in membranous nephropathy and mesangial proliferative glomerulonephritis pathological types were different. Conclusions Serum and urine ANGPTL8 levels in primary nephrotic syndrome patients were correlated with blood lipid levels and proteinuria, respectively, suggesting that ANGPTL8 may play a role in the development of primary nephrotic syndrome hyperlipidemia and proteinuria.
Cerebral palsy (CP) is a neurodevelopmental and motor disorder syndrome threatening children’s physical and mental health. Hypoxic-ischemic brain injury and inflammation have been considered as the main causes of CP. Mesenchymal stem cells (MSCs) can repair brain tissue damage, and many studies have proved that exosomes from MSCs have a critical advantage in the central nervous system (CNS) disease. Therefore, this study aimed to explore the improvement effect of human umbilical cord MSC (hUC-MSC)-derived exosomes on CP and whether synergistic action existed when combined with mouse nerve growth factor (mNGF). Therefore, the exosomes were isolated from hUC-MSCs and examined using electron microscopy, particle size, and Western blot (WB). A CP model was constructed by hypoxic induction after unilateral common carotid artery ligation combined with lipopolysaccharide (LPS) infection. The pathological damage of neuron tissue and synaptic structure in the hippocampus was determined using a light microscope after hematoxylin-eosin (HE) staining and transmission electron microscopy, respectively. The survival of neurons was analyzed using Nissl staining. The WB analysis was performed to monitor postsynaptic density 95(PSD-95) and synaptophysin(SYN) protein levels. The results showed that exosomes released by hUC-MSCs could ameliorate the motor function in mice with CP by rescuing the impaired brain tissue, synaptic structure, and neuronal function with increased PSD-95 and SYN levels. When the exosome was combined with mNGF, an improvement in CP was found. The results indicated that the intravenously injected hUC-MSC-exosomes and intraperitoneal administration of mNGF alleviated the nerve function injury in mice with CP.
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