Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A.

BACKGROUND: In glomerular hypertension, monocyte chemoattractant protein-1 (MCP-1) has been implicated in glomerulosclerosis progression. High-pressure load and stretch on mesangial cells (MC) are two major effects of increased glomerular pressure. We previously reported that pressure per se could induce MCP-1 expression in cultured MC, suggesting the involvement of glomerular hypertension in renal disease progression through MCP-1 expression in MC. We also showed that adrenomedullin (AM) inhibited pressure-induced MC proliferation; however, it is not clear whether AM alters pressure-induced mesangial MCP-1 expression. In this study, we examined the effect of AM on pressure-induced MCP-1 expression in cultured rat MC and the mechanism of such action. Using compressed helium, pressure was applied to MC placed in a sealed chamber. AM inhibited pressure-induced MCP-1 mRNA expression, measured by reverse transcribed-polymerase chain reaction (RT-PCR), in a dose-dependent manner. This inhibition was in parallel to an increase in cellular cyclic AMP (cAMP) levels evoked by AM. The effects of forskolin and dibutyryl cAMP mimicked those of AM. Protein kinase A (PKA) inhibitor H-89 significantly weakened the effects of AM. AM significantly reduced the pressure-induced increase in MCP-1 protein in supernatants of cultured MC, measured by enzyme-linked immunosorbent assay (ELISA). Our results suggested that AM inhibits pressure-induced mesangial MCP-1 expression through PKA activation.

Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease.

BACKGROUND: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. PATIENTS AND METHODS: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. RESULTS: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = -0.756, p < 0.0001). CONCLUSIONS: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.