Alterations of Intrarenal Adrenomedullin and Its Receptor System in Heart Failure Rats

Abstract

Abstract-Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion. Key Words: adrenomedullin Ⅲ receptors, adrenomedullin Ⅲ kidney Ⅲ heart failure Ⅲ sodium A drenomedullin (AM) and its gene expression have been reported to be observed in the glomerulus, distal tubules, and medullary collecting duct cells with respect to limitation to the kidney. [1][2][3][4] The AM infusion studies revealed that AM increased renal blood flow, urine flow, and urinary sodium excretion (UNaV) and decreased proximal and distal fractional reabsorption of sodium. 5-9 Furthermore, AM has been shown to inhibit DNA synthesis 10,11 and endothelin production 12 and to stimulate cAMP formation 13 in mesangial cells and renal tubular cells. 14,15 These findings suggest that AM may elicit its action as an autocrine and/or a paracrine factor as well as a circulating factor in the kidney. However, the specific AM receptor that mediates these many AM functions was only recently elucidated. McLatchie et al 16 demonstrated that the calcitonin receptor-like receptor (CRLR), a receptor with 7 transmembrane domains, can function as either a calcitonin gene-related peptide (CGRP) receptor or an AM receptor, depending on which members of a new family of single-transmembrane-domain proteins, which are called receptor-activity-modifying proteins (RAMPs) are expressed. RAMP1 presents the receptor at the cell surface as a CGRP receptor, whereas RAMP2-or RAMP3-transported receptors ...

Cardioprotective Effect of Adrenomedullin in Heart Failure

“…A recent study reported that the mRNA levels of CRLR, RAMP2, and AM are increased in the atrium and ventricle in rats with heart failure (26). Another study showed that the expression of the AM receptor component gene is not altered in the kidney in rats with heart failure, despite the increase of AM gene expression (27). We also found that the expression levels of the AM, CRLR, RAMP2, and RAMP3 genes were increased in the hypertrophied heart induced by malignant hypertension (28).…”

Adrenomedullin in Heart Failure

“…Interestingly, there was a significant positive association between urine sodium excretion and renomedullary adrenomedullin levels (27). Jougasaki and colleagues, in their study on dogs with rapid ventricular pacing-induced heart failure, observed that adrenomedullin immunoreactivity appeared to be increased at various sites within the kidney (28).…”

“…In regard to the kidney in heart failure, Yoshihara and colleagues reported that renal adrenomedullin levels were augmented in decompensated heart failure due to aortocaval shunts in rats, although RAMP 2 and RAMP 3 mRNA levels were not different between controls and heart failure animals (27). Interestingly, there was a significant positive association between urine sodium excretion and renomedullary adrenomedullin levels (27).…”

“…Similar actions may, of course, exist within blood vessels and in the kidneys. In the case of the kidneys, it is also possible that enhanced adrenomedullin expression and activity contribute to the preservation of urine sodium excretion (27).…”

Renoprotective Effect of Chronic Adrenomedullin Infusion in Dahl Salt-Sensitive Rats

“…Immediately after the heart was arrested by the injection of 2 mmol KCl, the left kidney was perfused with 30 mL of cold phosphatebuffered saline (pH 7.4) as previously reported and separated into the cortex and medulla, 12 frozen in liquid nitrogen, and stored at Ϫ80°C. The radioimmunoassay (RIA) for angiotensin II in renal cortical tissues was performed as reported previously.…”