MicroRNAs (miRNAs) are endogenous small RNAs that play an important role in various physiological processes by downregulating target genes. Recently, plasma miRNAs have been investigated as biomarkers for various diseases. In this study, miRNA array analysis in various tissues showed that miR-124 is almost exclusively expressed in the central nervous system and neuronal cells, suggesting that it might be useful as a potential biomarker for neurological diseases. We examined whether plasma concentrations of brain-specific miRNA can serve as a biomarker for cerebral infarction, where the cerebral infarction was modeled by middle cerebral artery occlusion (MCAO) in the rat. Plasma concentrations of miR-124 were significantly elevated at 6 h, and remained elevated at 48 h after MCAO introduction. Thus, plasma concentration of miR-124 provides a promising candidate biomarker for early detection of cerebral infarction.

MicroRNAs (miRNAs) are endogenous small RNAs that are 18-23 nucleotides long. Recently, plasma miRNAs were reported to be sensitive and specific biomarkers of various pathological conditions. In the present study, we focused on miR-210, which is known to be induced by hypoxia and might therefore be an excellent biomarker for congestive heart failure. Plasma miR-210 levels and expression levels in mononuclear cells and skeletal muscles were elevated in Dahl salt-sensitive rats with heart failure. We also assessed miR-210 expression in patients with heart failure. The miR-210 expression levels in the mononuclear cells of patients with NYHA III and IV heart failure according to the New York Heart Association (NYHA) functional classification system were significantly higher than those with NYHA II heart failure and controls. Although no significant correlation was observed between plasma brain natriuretic peptide (BNP) and plasma miR-210 levels in patients with NYHA II heart failure, patients with an improved BNP profile at the subsequent hospital visit were classified in a subgroup of patients with low plasma miR-210 levels. Plasma miR-210 levels may reflect a mismatch between the pump function of the heart and oxygen demand in the peripheral tissues, and be a new biomarker for chronic heart failure in addition to plasma BNP concentrations.

The P2X(7) receptor is a ligand-gated ion channel, and genetic variations in the P2X(7) gene significantly affect blood pressure. P2X(7) receptor expression is associated with renal injury and inflammatory diseases. Uninephrectomized wild-type (WT) and P2X(7)-deficient (P2X(7) KO) mice were subcutaneously implanted with deoxycorticosterone acetate (DOCA) pellets and fed an 8% salt diet for 18 days. Their blood pressure was assessed by a telemetry system. The mice were placed in metabolic cages, and urine was collected for 24 h to assess renal function. After 18 days of DOCA-salt treatment, P2X(7) mRNA and protein expression increased in WT mice. Blood pressure in P2X(7) KO mice was less than that of WT mice (mean systolic blood pressure 133 ± 3 vs. 150 ± 2 mmHg). On day 18, urinary albumin excretion was lower in P2X(7) KO mice than in WT mice (0.11 ± 0.07 vs. 0.28 ± 0.07 mg/day). Creatinine clearance was higher in P2X(7) KO mice than in WT mice (551.53 ± 65.23 vs. 390.85 ± 32.81 μl·min(-1)·g renal weight(-1)). Moreover, renal interstitial fibrosis and infiltration of immune cells (macrophages, T cells, B cells, and leukocytes) were markedly attenuated in P2X(7) KO mice compared with WT mice. The levels of IL-1β, released by macrophages, in P2X(7) KO mice had decreased dramatically compared with that in WT mice. These results strongly suggest that the P2X(7) receptor plays a key role in the development of hypertension and renal disease via increased inflammation, indicating its potential as a novel therapeutic target.

The P2X 7 receptor is a ligand-gated ion channel activated by extracellular ATP, and a common genetic variation in the P2X 7 gene significantly affects blood pressure. P2X 7 receptor expression is associated with renal injury and some inflammatory diseases. Brilliant blue G (BBG) is a selective rat P2X 7 receptor antagonist. In this study, to test whether BBG has protective effects on saltsensitive hypertension and renal injury, Dahl salt-sensitive (DS) rats fed an 8% NaCl diet were i.p. injected with BBG (50 mg kg À1 per day) for 4 weeks. We also tested another P2X 7 receptor antagonist, namely A-438079 (100 mg kg À1 per day), for 7 days. We found that P2X 7 antagonism markedly attenuated salt-sensitive hypertension, urinary protein or albumin excretion, renal interstitial fibrosis and macrophage and T-cell infiltration in the DS rats, and significantly improved creatinine clearance. In an in vitro experiment using macrophages, we showed that lipopolysaccharide (LPS)-primed macrophages from the DS rats released more interleukin-1 beta in response to BzATP, a P2X 7 receptor agonist, than the macrophages from Lewis rats, possibly due to higher P2X 7 expression in the DS rats. In conclusion, in vivo blockade of P2X 7 receptors attenuated salt-sensitive hypertension and renal injury in the DS rats. Thus, P2X 7 appears to be responsible for a vicious cycle of salt-sensitive hypertension and renal injury in the DS rats, through higher expression in the immune cells. Furthermore, P2X 7 antagonists can prevent the development of salt-sensitive hypertension and renal injury, thus confirming that the P2X 7 receptor is an important therapeutic target. INTRODUCTIONThe P2X 7 receptor is an adenosine-5¢-triphosphate (ATP)-gated cation channel that is expressed mainly in certain immune cells, including macrophages and lymphocytes. 1,2 Stimulation of P2X 7 is proinflammatory, resulting in the release of inflammatory cytokines, such as interleukin (IL)-1 beta (b) and IL-18 from macrophages 2-5 and IL-2 from T cells, 5-7 as well as changes in the plasma membrane lipid distribution and cell death by necrosis or apoptosis. 2,3 P2X 7 has been reported to be involved in various nephropathy models, such as glomerular injury caused by diabetes and hypertension, 8 unilateral ureteral obstruction 9 and glomerulonephritis. 10 Dahl salt-sensitive (DS) rats fed on a high-sodium diet characteristically develop attenuated pressure natriuresis, hypertension and progressive renal injury, and this model has been widely used to study salt-sensitive hypertension. 11,12 In a previous study, we performed a genome-wide quantitative trait locus mapping analysis for blood pressure by using F2 rats derived from DS and Lewis (LEW) rats, and we identified a region on chromosome 12 near the D12Arb6 marker that influenced blood pressure. 13 The P2X 7 gene is also near the D12Arb6 marker. A common genetic variation in the region of the P2X 7 gene significantly affects blood pressure in a Caucasian population. 14 Although the pathophysiology of hypertension...

Hepatic triglyceride (TG) accumulation is considered to be a prerequisite for developing nonalcoholic fatty liver (NAFL). Peroxisomes have many important functions in lipid metabolism, including fatty acid β-oxidization. However, the pathogenic link between NAFL and peroxisome biogenesis remains unclear. To examine the molecular and physiological functions of the Pex11α gene, we disrupted this gene in mice. Body weights and hepatic TG concentrations in Pex11α(-/-) mice were significantly higher than those in wild-type (WT) mice fed a normal or a high-fat diet. Hepatic TG concentrations in fasted Pex11α(-/-) mice were significantly higher than those in fasted WT mice. Plasma TG levels increased at lower rates in Pex11α(-/-) mice than in WT mice after treatment with the lipoprotein lipase inhibitor tyloxapol. The number of peroxisomes was lower in the livers of Pex11α(-/-) mice than in those of WT mice. Ultrastructural analysis showed that small and regular spherically shaped peroxisomes were more prevalent in Pex11α(-/-) mice fed normal chow supplemented without or with fenofibrate. We observed a significantly higher ratio of empty peroxisomes containing only PMP70, a peroxisome membrane protein, but not catalase, a peroxisome matrix protein, in Pex11α(-/-) mice. The mRNA expression levels of peroxisomal fatty acid oxidation-related genes (ATP-binding cassette, subfamily D, member 2, and acyl-CoA thioesterase 3) were significantly higher in WT mice than those in Pex11α(-/-) mice under fed conditions. Our results demonstrate that Pex11α deficiency impairs peroxisome elongation and abundance and peroxisomal fatty acid oxidation, which contributes to increased lipid accumulation in the liver.