epidermal-growth-factor and Glomerulonephritis

Glomerular kidney diseases are of major public health importance because of their strong impact on the quality of life of patients and of their costly management. A relatively neglected area of study is the local factors that influence development of glomerular demolition. The involvement of a glomerular factor has been now demonstrated in glomerulonephritis with cell proliferation such as crescentic rapidly progressive glomerulonephritis (RPGN). Various unrelated immune disorders promote RPGN, such as antibodies directed against the glomerular basement membrane, deposition of immune complexes or antibodies directed against neutrophils. Despite the heterogeneity of these causing diseases, RPGNs share similar histopathological features, which suggest involvement of common final pathways. De novo expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in glomerular epithelial cells is found specifically in human glomerulonephritis with proliferation of these cells and dedifferentiation of podocytes. A receptor for HB-EGF, the EGF receptor (EGFR), is expressed by parietal epithelial cells and podocytes. Furthermore, in a mouse model of RPGN, HB-EGF deficiency or conditional targeting of the Egfr alleles in podocytes markedly alleviated RPGN, renal failure and death. This indicates that the HB-EGF/EGFR pathway plays a pivotal role in RPGN and opens therapeutic perspectives as EGFR inhibitors are clinically available.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Glomerulonephritis; Humans; Kidney Glomerulus; Mice

Glomerulonephritis (GN) is a group of inflammatory diseases and an important cause of morbidity and mortality worldwide. The initiation of the inflammatory process is quite different for each type of GN; however, each GN is characterized commonly and variably by acute inflammation with neutrophils and macrophages and crescent formation, leading to glomerular death. Toll-like receptor (TLR) 7 is a sensor for self-RNA and implicated in the pathogenesis of human and murine GN. Here, we show that TLR7 exacerbates glomerular injury in nephrotoxic serum nephritis (NTN), a murine model of severe crescentic GN. TLR7

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Glomerulonephritis; Humans; Macrophages; Mice; Toll-Like Receptor 7

The balance of several cytokines likely influences the resolution of glomerulonephritis. Monocyte chemoattractant protein-1(MCP-1) is a chemokine that promotes renal inflammation whereas epidermal growth factor (EGF) stimulates protective responses. Previously, high urine MCP-1(MCP-1) and low urine EGF (EGF) levels were found to be associated with tubulointerstitial fibrosis, but there is limited information on the value of these mediators as predictors of therapeutic responses or long term outcome in primary glomerulonephritis.. To determine the performance of urine EGF, MCP-1 or their ratio at baseline as biomarkers to predict complete remission, and the relationship of these mediators with subsequent renal function 24 months later in primary glomerulonephritis.. This is a prospective study of patients with biopsy-proven primary glomerulonephritis. Baseline urine samples were collected at biopsy before therapy. MCP-1 and EGF were analyzed by enzyme-linked immunosorbent assays and expressed as a ratio to urine creatinine (ng/mgCr) or as EGF/MCP-1 ratio (ng/ng). Proteinuria and estimated glomerular filtration rate (eGRF) were monitored after therapy. Complete remission (CR) was defined as proteinuria ≤ 0.3 g/gCr.. Median follow-up was 20 months. Of all patients (n = 74), 38 patients (51.4%) subsequently achieved CR. Baseline urine EGF and EGF/MCP-1 levels were significantly higher in CR compared to Not CR. By contrast, MCP-1 was not different. High EGF (EGF > 75 ng/mgCr) was a significant predictor (OR 2.28) for CR by multivariate analysis after adjusting for proteinuria, blood pressure, baseline eGFR. In patients who completed 24 months follow-up (n = 43), baseline EGF correlated inversely with proteinuria and positively with eGFR at 24 months.. High urine EGF level is a promising biomarker of CR. Baseline EGF levels correlated with kidney function at 2 years. EGF/MCP-1 was not superior to EGF alone. Further studies are necessary to determine the role of urine EGF as a guide to therapy in primary GN.

Topics: Biomarkers; Chemokine CCL2; Cytokines; Epidermal Growth Factor; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis; Humans; Male; Middle Aged; Multivariate Analysis; Proteinuria; Remission Induction; ROC Curve

The degree of tubular atrophy and interstitial fibrosis (IFTA) is an important prognostic factor in glomerulonephritis. Imbalance between pro-inflammatory cytokines such as monocyte chemoattractant protein- 1 (MCP-1) and protective cytokines such as epidermal growth factor (EGF) likely determine IFTA severity. In separate studies, elevated MCP-1 and decreased EGF have been shown to be associated with IFTA severity. In this study, we aim to evaluate the predictive value of urinary EGF/MCP-1 ratio compared to each biomarker individually for moderate to severe IFTA in primary glomerulonephritis (GN).. Urine samples were collected at biopsy from primary GN (IgA nephropathy, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy). MCP-1 and EGF were analyzed by enzyme-linked immunosorbent assay.. EGF, MCP-1 and EGF/MCP-1 ratio from primary GN, all correlated with IFTA (n=58). By univariate analysis, glomerular filtration rate, EGF, and EGF/MCP-1 ratio were associated with IFTA. By multivariate analysis, only EGF/MCP-1 ratio was independently associated with IFTA. EGF/MCP-1 ratio had a sensitivity of 88% and specificity of 74 % for IFTA. EGF/MCP-1 had good discrimination for IFTA (AUC=0.85), but the improvement over EGF alone was not significant.. EGF/MCP-1 ratio is independently associated IFTA severity in primary glomerulonephritis, but the ability of EGF/MCP-1 ratio to discriminate moderate to severe IFTA may not be much better than EGF alone.

Topics: Adult; Atrophy; Biomarkers; Chemokine CCL2; Epidermal Growth Factor; Female; Fibrosis; Glomerulonephritis; Humans; Kidney Tubules; Male; Middle Aged; Sensitivity and Specificity; Severity of Illness Index

Activation of signal transducer and activator of transcription (STAT)3 correlates with proliferation of extracapillary glomerular epithelial cells and the extent of renal injury in glomerulonephritis. To delineate the role of STAT3 in glomerular epithelial cell proliferation, we examined the development of nephrotoxic serum-induced glomerulonephritis in mice with and without podocyte-restricted STAT3 deletion. Mice with STAT3 deletion in podocytes developed less crescents and loss of renal function compared with those without STAT3 deletion. Proliferation of glomerular cells, loss of podocyte markers, and recruitment of parietal epithelial cells were found in nephritic mice without STAT3 deletion, but mitigated in nephritic mice with podocyte STAT3 deletion. Glomerular expression of pro-inflammatory STAT3 target genes was significantly reduced in nephritic mice with, compared with those without, podocyte STAT3 deletion. However, the extent of glomerular immune complex deposition was not different. Podocytes with STAT3 deletion were resistant to interleukin-6-induced STAT3 phosphorylation and pro-inflammatory STAT3 target gene expression. Thus, podocyte STAT3 activation is critical for the development of crescentic glomerulonephritis.

Topics: Albuminuria; Animals; Antigen-Antibody Complex; Apoptosis; Cell Line; Cell Proliferation; Complement C3; Disease Models, Animal; Epidermal Growth Factor; Glomerulonephritis; Immunoglobulins; Inflammation Mediators; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Podocytes; Primary Cell Culture; Serum; Signal Transduction; STAT3 Transcription Factor; Time Factors

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, is expressed during inflammatory and pathological conditions. We have cloned the rat HB-EGF and followed the expression of HB-EGF in rat kidneys treated with anti- glomerular basement membrane (anti-GBM) antibody (Ab) to induce glomerulonephritis (GN). We observed glomerular HB-EGF mRNA and protein within 30 minutes of Ab administration and showed by in situ hybridization that glomerular HB-EGF mRNA expression was predominantly in mesangial and epithelial cells. Expression of HB-EGF correlated with the onset of decreased renal function in this model. To test the direct effect of HB-EGF on renal function, we infused the renal cortex with active rHB-EGF, prepared from transfected Drosophila melanogaster cells. This treatment induced a significant decrease in single nephron GFR (SNGFR), single nephron plasma flow, and glomerular ultrafiltration coefficient and an increase in the glomerular capillary hydrostatic pressure gradient. In addition, anti-HB-EGF Ab administered just before anti-GBM Ab blocked the fall in SNGFR and GFR at 90 minutes without any change in the glomerular histologic response. These studies suggest that HB-EGF expressed early in the anti-GBM Ab GN model contributes to the observed acute glomerular hemodynamic alterations.

Topics: Animals; Epidermal Growth Factor; Gene Expression Regulation; Gene Transfer Techniques; Glomerular Filtration Rate; Glomerulonephritis; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Rats; RNA, Messenger

In this study, we attempted to determine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) was up-regulated in two chronic models of proteinuria.. Chronic passive Heymann nephritis (PHN) and puromycin aminonucleoside (PAN) models were induced in Sprague-Dawley rats. HB-EGF expression was studied by Northern blotting, in situ hybridization, and immunohistochemistry.. The chronic PAN model was associated with the development of glomerular lesions of focal glomerular sclerosis (FGS), severe interstitial fibrosis, and renal failure. Lesions of FGS were seen in approximately 80% of glomeruli at all time points, with a slight increase in the number of glomeruli showing extensive adhesion between 40 and 90 days. Northern blots of whole kidney tissue showed a 3- to 5.8-fold increased expression of HB-EGF mRNA in the chronic PAN group. Increased mRNA and protein were localized by in situ hybridization and immunohistochemistry to tubules, glomerular epithelial cells (GECs), and cells of Bowman's capsule. HB-EGF mRNA and protein were strongly expressed by epithelial cells involved in the formation of the lesions of FGS. By contrast, in chronic PHN, there was a small increase in HB-EGF, and the extensive lesions of FGS did not develop despite continued, heavy proteinuria.. These data suggest that HB-EGF may contribute to formation of the lesions of FGS, perhaps through stimulation of abortive mitogenesis in GECs or an adhesive interaction between transmembrane HB-EGF and the exposed glomerular basement membrane.

Topics: Actins; Animals; Creatinine; Disease Models, Animal; Epidermal Growth Factor; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Heparin-binding EGF-like Growth Factor; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Macrophages; Male; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a new member of the EGF family, is mitogenic for several types of cells, through binding to cell surface heparan sulphate proteoglycans. This study has attempted to delineate HB-EGF expression by mesangial cells and to identify its role in experimental and human glomerulonephritis. Rat mesangial cells, cultured in the presence of phorbol acetate, hydrogen peroxide, interleukin-1beta, and tumour necrosis factor-alpha, expressed HB-EGF mRNA. Recombinant HB-EGF stimulated rat mesangial cells to proliferate and to express types I and III collagen. In the rat anti-Thy-1.1 nephritis, glomerular HB-EGF mRNA was up-regulated and peaked at days 5-7; its expression at the protein level in the glomerulus was prominent at days 5-10. By immunofluorescence, HB-EGF was positive predominantly in the mesangial area of renal tissues from 23 of 45 patients with various types of human glomerulonephritis, showing a significant correlation with the grade of mesangial proliferation; there was no staining in tissues from patients with minimal change nephrotic syndrome and normal kidney tissues. These data provide the evidence that HB-EGF is synthesized and expressed by mesangial cells and stimulates mesangial cell proliferation and collagen synthesis in vitro. HB-EGF is a potential mediator in mesangial cell proliferation and matrix expansion in experimental and human glomerulonephritis.

Topics: Animals; Cell Culture Techniques; Collagen; DNA; Epidermal Growth Factor; Gene Expression; Glomerular Mesangium; Glomerulonephritis; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Isoantibodies; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger

Tamm-Horsfall protein (THP) and epidermal growth factor (EGF) are both synthesized by tubular cells in the distal part of the nephron and excreted with the urine. The present study examines the urinary excretion rates of the two peptides in relation to functional tubular markers in patients with chronic nephropathy. Four groups of patients with moderate to severely reduced renal function were studied: glomerulonephritis (n = 10), diabetic nephropathy (n = 11), tubulointerstitial nephropathy (n = 13), and polycystic kidney disease (n = 8). The renal function was evaluated by glomerular filtration rate (GFR) as an indicator for the general renal function, lithium clearance (C(Li)) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADR(Na)) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, C(Li) and ADR(Na) (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, C(Li) and ADR(Na) were weaker (Spearman coefficients of variation 0.68, 0.42, and 0.44). When the effect of GFR had been accounted for by multiple variance analyses, the excretion rates of the two peptides were still associated with ADR(Na) but not with C(Li). In conclusion, the urinary excretion rates of especially EGF but also those of THP were correlated with renal function and distal tubular reabsorption of sodium in patients with chronic nephropathy.

Topics: Adjuvants, Immunologic; Adult; Aged; Diabetic Nephropathies; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Tubules, Distal; Kidney Tubules, Proximal; Loop of Henle; Male; Middle Aged; Mucoproteins; Polycystic Kidney Diseases; Uromodulin

Topics: Adult; Cell Division; Epidermal Growth Factor; Female; Glomerulonephritis; Humans; Male; Middle Aged

Topics: Animals; Epidermal Growth Factor; Glomerulonephritis; Growth Substances; Humans; Interleukins; Platelet-Derived Growth Factor; Transforming Growth Factors; Tumor Necrosis Factor-alpha

Radioimmunoassay for epidermal growth factor (EGF) was performed using the homogenates of glomeruli and tubular preparations obtained from normal human kidneys. EGF-immunoreactive material was 3- to 5-fold higher in the glomerular fractions than in the tubular fraction. By indirect immunofluorescence with a monoclonal antibody, EGF was positive in three of five normal human kidney tissues and in tissues of 24 of 33 patients with proliferative and nonproliferative types of glomerular diseases. Acid-urea treatment of tissue sections to unmask a hidden epitope of the EGF molecule disclosed EGF immunoreactivity in four more kidney specimens. EGF was localized along the glomerular capillary walls and was also present in the arterioles and small arteries. Staining with three monoclonal antibodies recognizing two different epitopes of EGF receptor (EGF-R) was positive in tissues of 2 normal subjects and 15 patients with glomerular diseases. EGF-R was found along the glomerular capillary walls, in peritubular capillaries, and within the epithelial cells of distal tubules and collecting ducts. Immunoelectron microscopy with colloidal gold staining showed that EGF and EGF-R were localized in the plasma membrane of glomerular endothelial cells. Immunofluorescence with or without acid-urea denaturation showed coexpression of EGF and EGF-R in glomeruli of 1 normal subject and 12 patients. This study demonstrated the presence of EGF and EGF-R in human glomeruli. There was no obvious difference in EGF and EGF-R expression in glomeruli derived from normal or diseased state.

Topics: Antibodies, Monoclonal; Epidermal Growth Factor; ErbB Receptors; Fluorescent Antibody Technique; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Humans; Immunohistochemistry; Kidney Glomerulus; Microscopy, Electron; Radioimmunoassay

In Henoch-Schönlein purpura nephritis (HSPN), glomeruli may develop cellular "crescents" composed of infiltrating monocytes and proliferating renal epithelia. In this study, we demonstrate that peripheral human monocytes can release an epidermal growth factor (EGF)-like substance detectable by a radioreceptor assay, which recognizes both EGF and transforming growth factor-alpha (TGF-alpha), but not with a radioimmunoassay, which recognizes only EGF. Furthermore, we report that urine from pediatric patients during the acute phase of HSPN contains a similar EGF-like species in addition to the endogenous EGF which is normally present. The EGF-like material was not present in urine from nine healthy children or from six children with acute post-streptococcal glomerulonephritis. The extent of crescent formation in our patients is uncertain, since renal biopsy was performed in only one case. However, we speculate that the urinary material resembling TGF-alpha which appears during the acute phase of HSPN may derive from monocytes infiltrating the kidney.

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Epidermal Growth Factor; Glomerulonephritis; Humans; IgA Vasculitis; Streptococcal Infections