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OBJECTIVE -Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method.RESEARCH DESIGN AND METHODS -Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured.RESULTS -Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue.CONCLUSIONS -The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy. Diabetes Care 29:848 -852, 2006R ecently proposed mechanisms for the development of diabetic nephropathy include glomerular hyperfiltration (1), disorientation of intracellular signal transduction (2), and involvement of advanced glycation end products (3). Activation of the reninangiotensin system (RAS) by high glucose, mechanical stress, and proteinuria has been implicated in the major changes associated with diabetic nephropathy (4). Thus, renal tissue activation of RAS is thought to contribute to deterioration in renal function of diabetic nephropathy. Recently, a number of large-scale prospective studies have proven that blockade of the system with ACE inhibitors and angiotensin II receptor blockers (ARBs) retards the progression of diabetic nephropathy (5-11). Actually, several studies suggest that the RAS is activated especially at the early stage (12,13). However, from early studies, hyporeninemia has been well known as a typical state of circulatory RAS in diabetic subjects at the late stage (14,15). Although the tissue RAS is thought to be controlled independently of the circulatory RAS, this apparent paradox is still difficult to interpret. It is supposed that the tissue RAS is activated in contrast to the circulatory RAS, and several non-or semiquantitative evaluations were made. However, direct or quantitative evidence in human diabetic nephropathy is very scarce so far. Furthermore, new major components for RAS, renin receptor (RER) (16), and ACE2 (17) have emerged recently.The purpose of this study is to determine whether expression levels of RAS including RER and ACE2 differ between nondiabetic and diabetic human renal tissues with full quantitative evalua...

Our objective was to investigate the plasma levels of brain and atrial natriuretic peptides (BNP and ANP, respectively) in patients with septic shock/severe sepsis and to study the association of BNP and ANP levels with hemodynamic parameters, severity of the disease, and prognosis of those patients. This is a prospective case series study of 22 patients with septic shock, 11 patients with severe sepsis, and 20 healthy volunteers at the Department of Emergency and Critical Care Medicine, Nara Medical University Hospital, Japan. Blood collection was performed on admission and on days 1, 2, and 4. Plasma BNP and ANP levels were measured by radioimmunoassay. Right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and left ventricular stroke work index were determined using a thermodilution catheter. Acute Physiological and Chronic Health Evaluation II scores were calculated. Plasma levels of BNP and ANP were markedly elevated in patients with septic shock/severe sepsis compared with controls (BNP, 7 +/- 0.3 pg mL; ANP, 13 +/- 1 pg mL). In patients with septic shock, both BNP and ANP peaked on day 2 (BNP, 987 +/- 160 pg mL; ANP, 103 +/- 17 pg mL). Plasma levels of BNP on day 2 in patients with septic shock significantly correlated with right atrial pressure (r = 0.744, P < 0.01), mean pulmonary arterial pressure (r = 0.670, P < 0.01), pulmonary arterial wedge pressure (r = 0.709, P < 0.01), left ventricular stroke work index (r = -0.552, P < 0.05), Acute Physiological and Chronic Health Evaluation II score (r = 0.581, P < 0.01), and poor prognosis (P < 0.05). The optimal cutoff point for predicting mortality in patients with septic shock was a BNP level of 650 pg mL on day 2, in which sensitivity and specificity were 92% and 80%, respectively. Increased plasma levels of BNP may reflect not only the severity of myocardial depression but also the disease severity and could be of prognostic value in patients with septic shock.

Background-The delayed release of serum cardiac markers such as creatine kinase isoenzyme MB and equivocal early electrocardiographic changes have hampered a diagnosis of acute myocardial infarction (AMI) in the early phase after its onset. Therefore, a reliable serum biochemical marker for the diagnosis of AMI in the very early phase is desirable. Methods and Results-Serum samples were collected from the patients with AMI, unstable angina pectoris, stable angina pectoris, and other diseases. Levels of serum deoxyribonuclease I (DNase I) activity in the patients were determined. An abrupt elevation of serum DNase I activity was observed within approximately 3 hours of the onset of symptoms in patients with AMI, with significantly higher activity levels (21.7Ϯ5.10 U/L) in this group compared with the other groups with unstable angina pectoris (10.4Ϯ4.41 U/L), angina pectoris (10.8Ϯ3.70 U/L), and other diseases (9.22Ϯ4.16 U/L). Levels of the DNase I activity in serum then exhibited a marked time-dependent decline within 12 hours and had returned to basal levels within 24 hours. Conclusions-We suggest that serum DNase I activity could be used as a new diagnostic marker for the early detection of AMI. Key Words: myocardial infarction Ⅲ enzymes Ⅲ diagnosis I n patients with acute myocardial infarction (AMI), the infarct size is an important determinant of both mortality and morbidity. 1 When revascularization and thrombolytic therapies are initiated rapidly, there is a greater potential for reduction in the infarct size. The release of cardiac proteins from injured cardiac tissue into plasma has been used as a diagnostic marker for the exclusion or confirmation of AMI. 2 However, it is often difficult to make a diagnosis of AMI in the very early phase, ie, within 3 hours of onset. This is partly due to a delay in the appearance in the serum of the biochemical markers specific for myocardial damage. 2,3 Deoxyribonuclease I (DNase I, EC 3.1.21.1), one of the well-known enzymes, was the first enzyme to be recognized as specific for DNA. 4 One of its proposed roles is DNA breakdown during apoptosis. 5 DNase I has been detected in human myocardium, and it has been reported that the activity level increases in heart failure due to idiopathic dilated cardiomyopathy. 6 However, the association between serum DNase I activity level and coronary heart disease (CHD) has not yet been clarified. In the present study, we assessed the serum DNase I activity in patients with AMI and related CHD and found that there is a specific elevation of serum DNase I activity in the very early stages of AMI. Methods Patients and Sample CollectionWe assessed 53 consecutive Japanese patients with AMI admitted to our hospitals between September 2002 and May 2003. The clinical diagnosis of AMI and unstable angina pectoris (UAP) was made according to the European Society of Cardiology/American College of Cardiology Committee criteria. 7 The mean lapse time between the onset of symptoms and hospital admission was 10.7Ϯ13.8 hours. Emergent coronary ang...

The objectives of this study were to evaluate all the non-synonymous single nucleotide polymorphisms (SNPs) in the DNase I and DNase I-like 3 (1L3) genes potentially implicated in autoimmune diseases as a functional SNP in terms of alteration of the activity levels. We examined the genotype distributions of the 32 and 20 non-synonymous SNPs in DNASE1 and DNASE1L3, respectively, in three ethnic groups, and the effect of these SNPs on the DNase activities. Among a total of 44 and 25 SNPs including those characterized in our previous studies [Yasuda et al., Int J Biochem Cell Biol 42 (2010) 1216-1225; Ueki et al. Electrophoresis 32 (2012) 1465-1472], only four and one, respectively, exhibited genetic heterozygosity in one or all of the ethnic groups examined. On the basis of alterations in the activity levels resulting from the corresponding amino acid substitutions, 11 activity-abolishing and 11 activity-reducing SNPs in DNASE1 and two activity-abolishing and five activity-reducing SNPs in DNASE1L3 were confirmed as a functional SNP. Phylogenetic analysis showed that all of the amino acid residues in activity-abolishing SNPs were completely or well conserved in animal DNase I and 1L3 proteins. Although almost all non-synonymous SNPs in both genes that affected the catalytic activity showed extremely low genetic heterogeneity, it seems plausible that a minor allele of 13 activity-abolishing SNPs producing a loss-of-function variant in both the DNase genes would be a direct genetic risk factor for autoimmune diseases. These findings may have clinical implications in relation to the prevalence of autoimmune diseases.

Mineralocorticoid receptors (MRs) have been identified in the human cardiovascular tissues. We determined MR expression in the failing heart to clarify the mechanism of action of aldosterone antagonist in the treatment of congestive heart failure. MR protein and MR mRNA content were detected by immunohistochemical staining and in situ hybridization in the cardiac tissues. Immunohistochemical staining of the receptor, as well as in situ hybridization of MR mRNA, was dense in cardiomyocytes of the failing left ventricle as compared with the controls. The staining ratio of the cytoplasm to the interstitium showed that MRs were located mainly in the cytoplasm. The cytoplasm to the interstitium in the failing left ventricle was 1.53+/-0.13, which was significantly higher than that of the controls 1.25+/-0.19 (p<0.05). These findings suggest that the efficacy of aldosterone antagonists in treating congestive heart failure may be in part through blocking the MRs, which are upregulated in the failing heart.

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