adrenomedullin and Glomerulonephritis--IGA

Topics: Adrenomedullin; Adult; Glomerulonephritis, IGA; Humans; Kidney Function Tests; Peptides

IgA nephropathy (IgAN) is the most frequent form of glomerulonephritis worldwide. The role of oxidative stress and inflammation in the pathogenesis of IgAN has been reported. Intermedin (IMD) is a newly discovered peptide that is closely related to adrenomedullin. We have recently reported that IMD can significantly reduce renal ischemia/reperfusion injury by diminishing oxidative stress and suppressing inflammation. The present study was designed to explore whether IMD ameliorates IgAN via oxidative stress- and inflammation-dependent mechanisms. Our results showed that IMD administration resulted in the prevention of albuminuria and ameliorated renal pathomorphological changes. These findings were associated with (1) decreased renal TGF-β1 and collagen IV expression, (2) an increased SOD level and reduced MDA level, (3) the inhibition of the renal activation of NF-κB p65 and (4) the downregulation of the expression of inflammatory factors (TNF-α, MCP-1 and MMP-9) in the kidney. These results indicate that IMD in the kidney protects against IgAN by reducing oxidative stress and suppressing inflammation.

Topics: Adrenomedullin; Animals; Glomerulonephritis, IGA; Inflammation; Kidney; Male; Neuropeptides; Oxidative Stress; Rats, Sprague-Dawley; Treatment Outcome

Adrenomedullin (AM) immunostaining and gene expression have seldom been measured in human kidneys. Because previous studies have shown that AM exerts antiproliferative effects on rat mesangial cells in vitro and that urine AM levels are decreased in patients with chronic glomerulonephritis, we measured glomerular AM and its gene expression in patients with primary IgA nephropathy (IgAN). Glomerular AM was measured by immunohistochemical staining, and glomerular AM mRNA was measured by in situ hybridization. Plasma and urine AM were measured by radioimmunoassay. The results showed that both the intensity of immunostaining for glomerular AM and the glomerular expression of AM mRNA were significantly decreased in IgAN patients compared with normal controls (both P < .05). Similar results were not observed in patients with non-IgA MsPGN. Glomerular AM immunostaining and glomerular AM mRNA expression were significantly correlated ( P < .001), and both were negatively correlated with the number of glomerular cells ( P < .05 and < .01, respectively). Both glomerular AM immunostaining and glomerular AM mRNA expression were correlated with urine AM levels (both P < .001), but not with plasma AM levels. The urine AM level was significantly lower in IgAN patients than in normal controls ( P < .01), whereas the plasma level was not different between the 2 groups. Our findings indicate that glomerular production of AM was decreased in patients with IgA nephropathy and that this lack of glomerular AM may be related to the pathogenesis of this mesangial disease.

Topics: Adrenomedullin; Adult; Female; Gene Expression; Glomerulonephritis, IGA; Humans; Immunohistochemistry; In Situ Hybridization; Kidney Cortex; Kidney Glomerulus; Male; Peptides; Radioimmunoassay; RNA, Messenger

We measured mRNA levels of adrenomedullin (AM), C-type natriuretic peptide (CNP), vascular endothelial growth factor (VEGF), interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) in peripheral blood mononuclear cells (PBMC) of patients with IgA nephropathy. To evaluate these mRNA levels, we employed a real-time quantitative PCR method which was performed using a hybridization probe labeled with two fluorescence dyes. This strategy was found to afford the standard curves with a high correlation, suggesting that this method is useful for evaluations of mRNA levels. By this method, levels of AM, CNP, VEGF, IL-1beta and IL-6 mRNA in PBMC of 49 IgA nephropathy patients and 35 healthy volunteers were evaluated. Among the mRNAs examined, AM mRNA levels were significantly lower in severe-grade than in mild-grade IgA nephropathy patients. Furthermore, AM mRNA levels correlated with CNP mRNA levels in PBMC of patients with IgA nephropathy, and each peptide generated from these mRNAs has antiproliferative effects on mesangial cells. These data indicate that gene expression of AM in PBMC is regulated according to the pathophysiological states of IgA nephropathy and that decreased AM production may contribute to the progression of IgA nephropathy.

Topics: Adrenomedullin; Adult; Aged; Base Sequence; Case-Control Studies; DNA Primers; Endothelial Growth Factors; Gene Expression Regulation; Glomerulonephritis, IGA; Humans; Interleukin-1; Interleukin-6; Leukocytes, Mononuclear; Lymphokines; Middle Aged; Natriuretic Peptide, C-Type; Peptides; RNA, Messenger; Transcription, Genetic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In this study, we measured plasma and urinary adrenomedullin (AM) concentrations in 47 patients with IgA nephropathy. Controls were 39 healthy volunteers. Plasma and urinary AM values were measured by specific radioimmunoassay. The plasma AM concentrations were higher, and the urinary AM levels were lower in patients with IgA nephropathy than in healthy volunteers. Plasma AM concentrations showed a positive correlation with serum creatinine and blood urea nitrogen, whereas urinary AM levels correlated negatively with serum creatinine and blood urea nitrogen. The plasma AM concentrations showed a positive correlation with fractional excretions of sodium and potassium. Renal biopsy specimens of patients without renal failure were scored for activity (percentage of glomeruli demonstrating cellular crescent formation, degree of mesangial proliferation and interstitial infiltration; total score = 9). Urinary AM levels were shown to be lower in the group with a high activity (score 3-9) as compared with the group with a low activity (score 0-2) based on renal biopsy. Thus, urinary levels of AM are affected by the degree of the activity in IgA nephropathy, and AM may participate in the pathophysiology of IgA nephropathy.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Blood Urea Nitrogen; Creatinine; Glomerulonephritis, IGA; Humans; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides; Radioimmunoassay