BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Objective:To explore the characteristics of cerebellar metabolites of autistic children using the magnetic resonance spectrum (MRS) and analyze their correlation with clinical symptoms.Methods:An autism group ( n=14) and a control group ( n=8) both underwent bilateral MRS scans of their cerebella. The NAA, Cho and Cr absolute values were recorded along with the NAA/Cr and Cho/Cr ratios. Those values were correlated with clinical symptoms of autism (the CARS and ABC scales), as well as with age. Results:There were no significant differences between the two groups in cerebellar metabolite levels, but the autism group exhibited significantly higher Cho/Cr ratios in the right cerebellum than in the left. There was a significant positive correlation between the Cho/Cr ratio in the right cerebellum and CARS scores, and between the NAA/Cr ratio in the right cerebellum and age.Conclusions:There is metabolic abnormality in the left and right cerebellar hemispheres of autistic children. The metabolic abnormality is related to the severity of clinical symptoms. However, metabolism in the cerebellum improves gradually with age.

Objective To determine whether chronic stress could potentiate learning and memory impairment in old mice, and, if so, what the underlying mechanism is. Methods Sixty male mice were divided randomly into control group and chronic stress group. Mice in stress group were stressed everyday by one of the stressors including cold exposure, restraint, level shake and so on. The ability of learning and memory was determined by Morris water maze test, and the histopathologic changes in CA3 field of the hippocampus were examined under a light micro-scope. Serum corticosterone level was determined by enzyme-linked immunosorbent assay. Western blot was per-formed to determine the expression of β-site amyloid precursor protein-cleaving enzyme 1 and Aβ1-42 in hippocam-pus of the brain. Results Compared with the control group, the results showed that chronic stress could increase the escape latency and swimming distance of old mice during training session in the Morris water maze test. The neuropathological changes were characterized by the decreased neuron number,soma shrinkage and condensation,or nuclear pyknosis in the CA3 field of hippocampus in the stress group. On the other hand, the expression of Aβ1-42 and BACE1 protein in hippocampus were increased, as well as the serum corticosterone concentration in the stress group. Conclusion Chronic stress can potentiate learning and memory impairment and pathological damage in CA3 field of the hippocampus in old mice, which may be related to chronic stress up-regulated the levels of BACE1 and Aβ1-42 mediated by corticosterone.

With redox-sensitive fluorescene probes DCFH-DA and DHR123, the formation of cytosolic and intramitochondrial reactive oxygen species (ROS) inside immature rat cerebellar granule cells during the apoptosis induced by nitric oxide donor S-nitroso-N-acetyl-pennicillamine (SNAP) was monitored by laser confocal scanning microscopy. The cytosolic and intramitochondrial ROS increase significantly after 0.5 mmol/L SNAP treatment for 1 h. Pre-treatment with the nitric oxide scavenger hemoglobin can effectively inhibit the formation of cytosolic and intrarnitochondrial ROS and protect neurons from apoptosis. Adding glutathione can also protect neurons from apoptosis, and the cytotoxity of nitric oxide increases significantly while the synthesis of glutathione is inhibited. The results indicated that ROS might be involved in NO-induced apoptosis in neural cells and glutathione might be the endogenesis antioxidant to protect neurons from oxidative injury.