adrenomedullin and Glomerulonephritis

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

Adrenomedullin (ADM) has antiproliferative effects on glomerular mesangial cells. The study was performed to determine changes in glomerular gene expression of the ADM system by ADM treatment in anti-Thy1 glomerulonephritis (GN).. GN in rats was induced by injecting anti-Thy-1 antibody. To show the effect of ADM treatment, rats received ADM from day 3 to day 6 of GN. Supplemental rats were sacrificed on day 3, 7 and 14 of GN to show the expression pattern of adrenomedullin and its receptors. Glomeruli were prepared by sieving or laser-assisted microdissection. Expression of ADM, calcitonin receptor-like receptor (CLR), receptor activity-modifying proteins (RAMP) 1-3, CD34, Thy1 and nephrin was analyzed using real-time PCR.. During GN a reduction of CLR and RAMP 2 + 3 expressions was detected on days 3, 7 and 14, while RAMP 1 rose. ADM mRNA decreased on days 3 and 7. Thy1 expression as a surrogate of mesangial cell number was downregulated during GN. A significant reduction of CD34 expression, as a surrogate for endothelial cell number, was detected on day 7. A tendency towards reduction of nephrin gene expression, as a surrogate for number of podocytes, was seen. The administration of ADM during GN did not change the expression on Thy1, CD34 or nephrin. The results were similar for microdissected and sieved glomeruli. In ADM-treated GN animals ADM gene expression rose compared to untreated GN animals on day 6. These effects were detected both in sieved and microdissected glomeruli. ADM administration did not change the expression of the receptors.. The downregulation of adrenomedullin during GN at the gene level can be improved by ADM application.

Topics: Adrenomedullin; Animals; Antigens, CD34; Calcitonin Receptor-Like Protein; Down-Regulation; Glomerulonephritis; Intracellular Signaling Peptides and Proteins; Isoantibodies; Kidney Glomerulus; Male; Membrane Proteins; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, G-Protein-Coupled

The kidneys receive 20-25 % of cardiac output and play a main role in the control of cardiovascular homeostasis. It is an endocrine organ that regulates and produces many substances, scavenger particles and immune complexes. Cytokines, growth factors, reactive oxygen metabolites, bioactive lipids, proteases, vasoactive substances such as nitric oxide (NO), adrenomedullin (AM), urotensin-II (U-II), have been released in several diseases, and kidney is one of mostly affected organs in body. Some of these mediators act in a paracrine fashion while some act in autocrine. They play important roles in modulating the cardiovascular responses, renal hemodynamics, and probably in mediating the clinical and laboratory manifestations of several renal diseases. These mediators are like "a double edged sword". While small amounts of them mediate many physiological events, little excess may cause the damage to the healthy cells. Many investigators have searched the role(s) of mediators in several diseases. However, the findings are mostly like the model of "chicken and egg", and indistinguishable as to whether they are the causes of, or results of the diseases. We will discuss mainly the possible roles of NO, AM and U-II in children with several renal diseases and summarize what is known, and what must be known about these mediators.

Topics: Adolescent; Adrenomedullin; Child; Creatinine; Cytokines; Female; Glomerulonephritis; Hemodynamics; Humans; IgA Vasculitis; Kidney; Male; Nitric Oxide; Peptides; Urotensins

FTY720 has been originally developed as a new immunosuppressive agent, which prolongs graft survival in organ transplantation. Adrenomedullin (AM) participates in the regulation of sodium homeostasis and has renoprotective effects. The possible involvement of renal AM in the pathophysiology of glomerulonephritis (GN) and the effect of FTY720 has been evaluated in rats. HgCl2 (1 mg/kg body weight) was inoculated subcutaneously 3 times/week for a total of 2 weeks. FTY720 (3 or 10 mg/kg) was inoculated subcutaneously daily. The proteinuria, urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion and serum total cholesterol levels were increased and serum albumin level was reduced in rats with HgCl2-induced GN compared with controls. FTY720 reduced proteinuria (3 mg/kg: -25%; 10 mg/kg: -41%), urinary NAG excretion (-11%; -52%) and total cholesterol level (-21%; -55%) in a dose-dependent manner. Renal AM level and its mRNA expression were increased in rats with GN compared with controls (Peptide Cortex: +69%; Medulla: +82%; mRNA Cortex: +25%). Interestingly, FTY720 additionally increased these levels (Peptide Cortex: +38%; Medulla: +39%; mRNA Cortex: +20%). Renal AM levels correlated with urinary NAG excretion and creatinine clearance. These results suggest that FTY720 suppresses the renal damage in rats with GN and renal AM may participate in the pathophysiology of GN and the renoprotective effects of FTY720.

Topics: Adrenomedullin; Animals; Autoimmune Diseases; Blood Chemical Analysis; Fingolimod Hydrochloride; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney; Male; Mercuric Chloride; Peptides; Propylene Glycols; Proteinuria; Radioimmunoassay; Random Allocation; Rats; Sphingosine; Statistics as Topic; Urine

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor beta (TGF-beta) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine -87%, creatinine clearance +114%, urinary protein excretion -59%) and histological findings (glomerular injury score -54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (-97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (-269%), aldosterone level (-82%), and renal tissue angiotensin II levels (-60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-beta (- 63%), angiotensin-converting enzyme (-137%), renin (-230%), and angiotensinogen (-38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Topics: Adrenomedullin; Angiotensin II; Animals; Creatinine; Drug Implants; Glomerulonephritis; Hormones; Hypertension; Kidney; Male; Peptides; Proteinuria; Rats; Rats, Inbred Dahl; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride; Time Factors; Transforming Growth Factor beta

To investigate the influence of adrenomedullin (AM) on the biological events governed by transforming growth factorbeta (TGF-beta) in human tubular epithelial cell line (HK-2).. Cell proliferation was determined by (3)H-TdR incorporation; ELISA method was used to detect the level of secreted fibronectin (FN); total collagen synthesis and secretion were reflected by (3)H-proline incorporation and the radioactivity of (3)H-hydroproline in the culture medium; the expression of FN mRNA, collagen IV mRNA and TIMP-1mRNA was determined by RT-PCR; plasma AM was measured by radioimmunoassay.. (1) AM had no effect on cell growth inhibition of TGF-beta(1) (P > 0.05); (2) AM dose-dependently inhibited collagen synthesis and secretion stimulated by TGF-beta(1). As compared with those in TGF-beta group, collagen synthesis and secretion in AM (10(-8) mol/L group were inhibited by 8% (P > 0.05) and 30% (P < 0.05), respectively; and the collagen synthesis and secretion in AM (10(-7) mol/L) group were inhibited by 57% (P < 0.05) and 64% (P < 0.01), respectively in AM (10(-7) mol/L) group. Similarly, AM (10(-8) mol/L) inhibited the FN secretion (20 ng/microliter +/- 5 ng/microliter) stimulated by TGF-beta(1) (28 ng/microliter +/- 6 ng/microliter) (P < 0.05). RT-PCR showed that AM significantly down-regulated the expression of collagen IV, FN and TIMP-1 mRNA stimulated by TGF-beta(1). (3) The plasma AM in patients with mild tubulointerstitial lesion was 1. 2 times higher than that in normal controls. the plasma AM in patients with severe tubulointerstitial lesion was 2.2 times higher than that in normal controls. The plasma AM in patients with severe tubulointerstitial lesion was 50% higher than that in patients with mild tubulointerstitial lesion (P < 0.01).. AM antagonizes the biological action of TGF-beta(1) on extracellular matrix accumulation; plasma AM increases in glomerulonephritis patients and correlates with the degree of tubulointerstitial lesion.

Topics: Adolescent; Adrenomedullin; Adult; Cell Division; Cell Line; Collagen Type IV; Female; Fibronectins; Glomerulonephritis; Humans; Kidney Tubules; Male; Middle Aged; Peptides; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Transforming Growth Factor beta1

Adrenomedullin (AM) is a potent vasodilative and natriuretic peptide that is processed from its precursor as the intermediate form, AM-glycine-COOH (iAM). Subsequently, iAM is converted to the biologically active mature form, AM(1-52)-CONH(2) (mAM), by enzymatic amidation. Using immunoradiometric assays that recognize total AM (tAM) and only mAM, we determined the plasma and urinary levels of mAM and iAM in patients with chronic glomerulonephritis (CGN). The plasma mAM concentration was significantly higher in the patients than in the controls (1.8 +/- 0.1 vs. 1.3 +/- 0.1 fmol/ml, p < 0.01), whereas the plasma iAM concentration of the CGN patients did not significantly differ from that of the controls (9.4 +/- 0.5 vs. 8.9 +/- 0.5 fmol/ml). Levels of urinary mAM excretion in the patients did not statistically differ from those of the controls (1. 6 +/- 0.4 vs. 2.0 +/- 0.3 fmol/mg creatinine), whereas urinary iAM excretion was significantly lower in the CGN patients (3.7 +/- 0.7 vs. 5.6 +/- 0.8 fmol/mg creatinine, p < 0.05). Urinary excretion levels of mAM significantly correlated with those of sodium (r = 0. 47, p < 0.05), whereas those of iAM did not. In conclusion, the plasma ratio of mAM to iAM is augmented in CGN patients, and mAM appears to be involved in the regulation of sodium. Therefore, determination of the mAM in addition to the tAM concentration is essential in CGN patients.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Female; Glomerulonephritis; Humans; Immunoradiometric Assay; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Peptides; Protein Precursors; Proteins

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 +/- 0.17 v 3.87 +/- 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 +/- 0.95 v control, 8.93 +/- 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 +/- 0.08 v 1.23 +/- 0.20 fmol/mL; P < 0.05 and 25.0 +/- 3.0 v 35.0 +/- 3.6 fmol/mg of creatinine, respectively; P < 0. 05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = -0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r = 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

Topics: Adrenomedullin; Adult; Calcitonin Gene-Related Peptide; Case-Control Studies; Chronic Disease; Female; Glomerulonephritis; Humans; Male; Natriuresis; Peptide Fragments; Peptides; Proteins; Vasodilator Agents

Adrenomedullin (AM), a novel vasodilator peptide, is produced by C-terminal amidation reaction of AM-glycine. AM-glycine, an intermediate form of AM (iAM), is processed from pro AM. AM circulating in the human blood stream was found to consist of an amidated mature form (mAM) and iAM. Biological activity is exerted only by mAM.. To investigate the pathophysiological role of mAM in renal disease, we measured plasma concentrations of mAM as well as total AM (tAM), representing both mAM and iAM, in patients with various renal diseases. In addition, plasma ANP level was measured in all patients.. The concentrations of plasma mAM in renal failure with dialysis (2.1 +/- 0.2 fmol/ml, mean +/- SEM) and without dialysis (1.2 +/- 0.2) were significantly (p < 0.05) higher than those in control group (0.5 +/- 0.1). However, the plasma ANP level was increased only in renal failure patients with dialysis. Plasma mAM levels were significantly correlated positively with serum creatinine levels and negatively with hematocrit. No significant difference was noted in the ratio of mAM/tAM between renal failure patients and healthy subjects.. These results suggest that plasma mAM is increased in renal failure in relation to deterioration of renal function, while the amidation process of AM seems to be unaffected in patients with renal failure.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Creatinine; Erythropoietin; Female; Glomerulonephritis; Glycine; Hematocrit; Humans; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Peptides; Prodrugs; Recombinant Proteins; Renal Dialysis; Vasodilator Agents

In this study, we measured levels of plasma and urinary adrenomedullin (AM) in 37 patients with chronic glomerulonephritis including minimal change nephrotic syndrome, focal segmental glomerulosclerosis or membranous nephropathy that can induce severe proteinuria. Thirty-nine healthy volunteers were enrolled as controls. Plasma and urinary AM levels were measured by an AM-specific radioimmunoassay. Plasma AM concentrations were higher and urinary AM levels were lower in patients with chronic glomerulonephritis than in healthy volunteers. Patients were divided into two groups according to urinary excretion of protein for 24 h (UPro, g/day) which reflects the disease activity or glomerular damage of the glomerulonephritis (group I: Upro < 1, group II: Upro >= 1). Plasma AM levels positively and urinary AM-levels negatively correlated with the degree of proteinuria. These results suggest that plasma and urinary AM levels in patients with chronic glomerulonephritis reflect the disease activity or glomerular damage represented by the degree of proteinuria.

Topics: Adrenomedullin; Adult; Aged; Analysis of Variance; Case-Control Studies; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Middle Aged; Nephrotic Syndrome; Peptides; Proteinuria; Vasodilator Agents