Search

Adrenomedullin reflects cardiac dysfunction, excessive blood volume, and inflammation in hemodialysis patients. Background. Plasma adrenomedullin (AM) reflects cardiac dysfunction and predicts survival after myocardial infarction. The present study was designed to investigate whether the mature AM (mAM) reflects status of cardiac function, systemic blood volume, or inflammation in hemodialysis patients with cardiovascular disease, and whether mortality and additional cardiovascular morbidity can be predicted by mAM. Methods. Plasma levels of mAM, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), norepinephrine (NE), and C-reactive protein (CRP) before hemodialysis were measured in 67 chronic hemodialysis patients with cardiovascular disease, along with 2-dimensional and Doppler echocardiographic variables. Results. By univariate regression analysis, mAM correlated negatively with pulmonary venous flow velocity ratio and left ventricular (LV) ejection fraction and positively with LV inflow velocity ratio, LV end-diastolic, end-systolic volume indexes, plasma CRP level, and removal fluid volume by ultrafiltration. Multivariate stepwise regression analysis revealed that mAM reflected all variables better than log [ANP], log [BNP], and log [NE]. During a 1-year follow-up period, 7 patients died and 8 had additional cardiovascular events. Event-free Kaplan-Meier curves based on the median mAM (4.55 pmol/L) showed that patients with high plasma mAM levels had higher mortality and morbidity than those with low plasma mAM levels ( P= 0.0056). By Cox multivariate proportional hazard analysis, mAM was related to mortality and morbidity [hazard ratio (HR) 4.55, 95% CI 1.2-16.8, P= 0.023). Conclusion. Plasma mAM reflects cardiac dysfunction, excessive blood volume, and inflammation better than ANP, BNP, and NE, resulting in a predictor of mortality and cardiovascular morbidity in hemodialysis patients with cardiovascular disease. [ABSTRACT FROM AUTHOR]

The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. Background. Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. Methods. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. Results. STZ rats showed glomerular hypertrophy and increased urinary NO2− and NO3− excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 ± 360 fmol/day vs. control 110 ± 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. Conclusion. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Microsatellite DNA polymorphism of human adrenomedullin gene in type 2 diabetic patients with renal failure. Background. Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues such as the heart, kidney, and the vascular cells. We have previously cloned and sequenced the genomic DNA encoding human AM gene, and determined that the gene is located in the short arm of chromosome 11. The 3′-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to develop nephropathy in type 2 diabetes mellitus. Methods. Genomic DNA was obtained from the peripheral leukocytes of 233 normal healthy subjects (NH), 139 type 2 diabetic patients on hemodialysis (DM-HD), 106 control patients with type 2 diabetes without nephropathy (DM-C) and 318 hemodialysis patients due to chronic glomerulonephritis (CGN-HD). The genomic DNA was subject to polymerase chain reaction (PCR) using a fluorescence-labeled primer, and the number of CA repeats were determined by polyacrylamide gel electrophoresis (PAGE). Results. In our Japanese subjects, there existed four types of alleles with different CA-repeat number; 11, 13, 14, and 19. The frequencies of these alleles were 11: 27.7%, 13: 32.8%, 14: 35.6%, and 19: 3.9% in NH. These allele frequencies were not significantly different in DM-C and CGN-HD. However, DM-HD showed significantly different distribution of allele frequency from other groups (χ2 = 18.9, P = 0.026). Namely, the frequency of 19-repeat allele in DM-HD was higher (9.0%) than NH, DM-C, and CGN-HD (P = 0.005, 0.041, and 0.004, respectively). Conclusion. The microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to develop nephropathy in Japanese patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Adrenomedullin (AM) is a newly discovered peptide that has a potent vasorelaxant activity. To investigate its potential roles in hypoxia-induced renal injury, we examined whether AM production in the kidney increased under hypoxic conditions. Methods: The AM transcript levels in Madin-Darby canine kidney (MDCK) cells, rat vascular smooth muscle cells (VSMCs), and rat mesangial cells were assessed by Northern blot analyses under normoxic and hypoxic conditions. The AM peptide in culture media was measured by radioimmunoassay. The effects of hypoxia on accumulation of cAMP in VSMCs were also examined. The stability of AM transcripts under normoxic and hypoxic conditions was compared in the presence of actinomycin D. The effects of hypoxia on AM promoter activity was assessed by transient transfection assays using the AM promoter subcloned upstream of luciferase gene. Results: The expression of AM transcripts increased significantly in MDCK cells, rat VSMCs, and rat mesangial cells under hypoxic conditions without changes in the stability of AM transcripts; however, the AM promoter activity under hypoxic was not elevated significantly. The accumulation of AM peptide in culture media also increased significantly under hypoxic conditions in MDCK cells (2.2 +/- 0.1 fmol/10(5) cells in normoxia vs. 3.5 +/- 0.3 fmol/10(5) cells in hypoxia, 6 hr after hypoxia induction, P < 0.001), and in rat VSMCs (5.5 +/- 0.3 fmol/10(5) cells in normoxia vs. 7.8 +/- 0.4 fmol/10(5) cells in hypoxia, 8 hr after hypoxia induction, P < 0.01). Under hypoxic conditions, cAMP levels in rat VSMCs increased significantly compared with those under normoxic conditions (13.3 +/- 1.4 pmol/well vs. 4.6 +/- 0.4 pmol/well, P < 0.01). Conclusions: Renal parenchymal cells as well as renal vessels may produce AM under hypoxic conditions. [ABSTRACT FROM AUTHOR]