epidermal-growth-factor and Kidney-Diseases

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent an important challenge for healthcare providers. The identification of new biomarkers/pharmacological targets for kidney disease is required for the development of more effective therapies. Several studies have shown the importance of the endoplasmic reticulum (ER) stress in the pathophysiology of AKI and CKD. ER is a cellular organelle devolved to protein biosynthesis and maturation, and cellular detoxification processes which are activated in response to an insult. This review aimed to dissect the cellular response to ER stress which manifests with activation of the unfolded protein response (UPR) with its major branches, namely PERK, IRE1α, ATF6 and the interplay between ER and mitochondria in the pathophysiology of kidney disease. Further, we will discuss the relationship between mediators of renal injury (with specific focus on vascular growth factors) and ER stress and UPR in the pathophysiology of both AKI and CKD with the aim to propose potential new targets for treatment for kidney disease.

Topics: Acute Kidney Injury; Angiopoietins; Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Epidermal Growth Factor; Fibroblast Growth Factors; Golgi Apparatus; Humans; Kidney; Kidney Diseases; Mitochondria; Renal Insufficiency, Chronic; Unfolded Protein Response; Vascular Endothelial Growth Factor A

The effects of obstruction on renal function are the consequence of many factors that profoundly alter all components of glomerular function. Besides the acute effects on glomerular filtration rate and tubule function, a chronic obstruction induces tubular and interstitial injury that results from the activation of different pathways. The progression of tubulointerstitial injury leads to chronic renal damage characterized by tubular atrophy, inflammatory cell infiltration, and interstitial fibrosis. Obstructive nephropathy is an evolving disease in which the renal damage continues even after relief of the obstruction. In particular, it has been demonstrated that the time of relief is the most important factor in predicting long-term renal function deterioration. In this setting, the EGF/MCP-1 ratio, urinary NGAL, and urinary KIM-1 are useful early biomarkers of progressive renal damage and could have a potential role in predicting the long-term renal outcome. This minireview summarizes the role of these emerging urinary biomarkers of obstructive nephropathy based on the current understanding of the pathophysiology of renal injury.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Biomarkers; Chemokine CCL2; Epidermal Growth Factor; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney Diseases; Kidney Tubules; Lipocalin-2; Lipocalins; Membrane Glycoproteins; Proto-Oncogene Proteins; Receptors, Virus; Ureteral Obstruction

This review focuses on recent advances in understanding the factors contributing to obstructive nephropathy, the most important cause of renal failure in children. The major focus is on renal cellular and molecular events, with emphasis on those affecting the developing kidney.. Experiments in the fetal sheep or neonatal rat, mouse, or pig reveal dramatic effects of urinary tract obstruction on renal growth and development. Surgical relief of obstruction can reverse some of the structural and functional deficits, but cannot restore normalcy. Renal tubular apoptosis is a major factor leading to tubular atrophy following unilateral ureteral obstruction. Increased reactive oxygen species, and a renal environment favoring pro-apoptotic, over survival, signals, contribute to cell death. A variety of intrarenal factors lead to progressive interstitial fibrosis, including the newly described process of epithelial-mesenchymal transition, whereby tubular epithelial cells are transformed into activated fibroblasts. A number of endogenous antifibrotic counter-regulatory molecules have been identified, opening the possibility of enhancing the kidney's own defenses against progressive fibrosis.. The renal response to urinary tract obstruction is complex and involves a wide array of interacting molecules. Elucidation of these interactions will lead to the identification of biomarkers that will allow a more precise prediction to the response to surgical intervention and, hopefully, to novel therapies to prevent renal deterioration.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Connective Tissue Growth Factor; Death-Associated Protein Kinases; Disease Progression; Epidermal Growth Factor; Humans; Immediate-Early Proteins; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Kidney Tubules; Ureteral Obstruction

Obstructive nephropathy is one of the most important causes of renal failure in infants and children, while polycystic kidney disease (PKD) is a major cause of renal failure in the adult population. This review summarizes the evidence that there may be a number of mechanisms common to the pathophysiology of both conditions. In animal models of obstructive nephropathy and PKD, the renal tubular expression of epidermal growth factor is suppressed, and expression of clusterin is increased, both of which suggest arrested maturation or dedifferentiation of the tubular cell. There is a marked increase in apoptosis of epithelial cells in dilated tubules, associated with an increase in apoptotic stimuli. The renin-angiotensin system is activated in both obstructive nephropathy and PKD, which may contribute to tubular atrophy and interstitial fibrosis, which characterize the progression of both conditions. Focal cystic dilatation of the tubule is found in obstructive nephropathy, while tubular obstruction is present in cystic kidney disease. It is therefore likely that elucidation of the effects of mechanical stretch on renal tubular epithelial cells will contribute to our understanding of both conditions.

Topics: Adult; Animals; Apoptosis; Child, Preschool; Epidermal Growth Factor; Humans; Infant; Kidney Diseases; Kidney Tubules; Polycystic Kidney Diseases; Renin-Angiotensin System; Ureteral Obstruction

Topics: Animals; Apoptosis; Cell Division; Epidermal Growth Factor; ErbB Receptors; Kidney Diseases; Mice; Mice, Knockout; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Transcription Factor AP-1

Congenital obstructive nephropathy remains one of the most-important causes of renal insufficiency in children. This review focuses on the unique interactions that result from urinary tract obstruction during the period of renal development in the neonatal rodent. Following unilateral ureteral obstruction (UUO), growth of the obstructed kidney is impaired and compensatory growth by the intact opposite kidney is related directly to the duration of obstruction. Development of the renal vasculature is delayed by UUO, and the activity of the intrarenal renin-angiotensin system is enhanced throughout the period of obstruction. Glomerular maturation is also delayed by UUO, and nephrogenesis is permanently impaired. The effects of UUO on the developing tubule are also profound, with a suppression of proliferation, stimulation of apoptosis, and the maintenance of an immature phenotype by tubular epithelial cells. Expression of tubular epidermal growth factor is suppressed and transforming growth factor-beta1 and clusterin are increased. Maturation of interstitial fibroblasts is delayed, with progression of tubular atrophy and interstitial fibrosis resulting in part from continued activation of the renin-angiotensin system and oxygen radicals. Future efforts to prevent the consequences of congenital urinary tract obstruction must account for the dual effects of obstruction: interference with normal renal development and progression of irreversible tubulointerstitial injury.

Topics: Animals; Blood Vessels; Epidermal Growth Factor; Kidney; Kidney Diseases; Renin-Angiotensin System; Ureteral Obstruction

We selectively focus on two growth factors, epidermal growth factor (EGF) and insulin-like growth factor (IGF), and discuss their roles on regulation of renal function and associated diseases conditions, as well. EGF, 6 kD polypeptide, is derived by proteolysis from a large precursor (prepro EGF, 133 kD). Prepro EGF is a membrane-anchored protein and its mRNA is predominantly localized to distal tubules of mouse and rat kidneys. We immunohistochemically demonstrated the glomerular distribution of EGF and EGF-receptor in normal and nephritic human kidneys. The physiologic roles of EGF produced in the kidney are various; it is mitogenic for tubular epithelial cell, inhibits gluconeogenesis and salt and water reabsorption in the tubules, and effects on glomerular hemodynamics. Alteration of renal EGF expression is suggested in renal ischemic injury, renal hypertrophy and cystic renal disease. IGF-I, somatomedin-C, is produced in collecting duct, and glomerular cells, and exerts a variety of actions on kidney. IGF-I stimulates gluconeogenesis in renal tubules, and is mitogenic for mesangial cells. The administration of this growth factor increases glomerular filtration rate. Enhanced expression of renal IGF-I was observed in the uninephrectomized animals.

Topics: Animals; Electrolytes; Epidermal Growth Factor; ErbB Receptors; Glomerular Filtration Rate; Gluconeogenesis; Humans; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Kidney Glomerulus

Topics: Adult; Aged; Endocrine System Diseases; Epidermal Growth Factor; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Neoplasms; Radioimmunoassay; Radioligand Assay

To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin.. Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospective, randomized, double-blind, placebo-controlled trial. Twenty-one patients received dopamine, and 21 received placebo. Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo. Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine (group D) or placebo (group P). This schedule was repeated twice, 1 week apart. Measurements of serum creatinine, urinary electrolytes and creatinine, urinary excretion of epidermal growth factor (EGF), ototoxicity, parameters of hematopoietic recovery, and duration of hospitalization were analyzed.. We observed an increase in serum creatinine level to a peak of 1.9 mg/dL (range, 0.8 to 7.8) in the dopamine group, in comparison to 1.4 mg/dL (range, 0.9 to 3.3) in the placebo group (P = .04). Urinary magnesium excretion increased and EGF excretion decreased in both groups. Urinary sodium, chloride, and potassium excretion were increased in both groups, but more so in the placebo group. Dopamine had no measurable effect on hearing loss, duration of hospitalization, or hematopoietic recovery.. The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity. Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a randomized prospective trial.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Creatinine; Cyclophosphamide; Dopamine; Double-Blind Method; Electrolytes; Epidermal Growth Factor; Etoposide; Female; Hearing Loss; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Water-Electrolyte Imbalance

Urine biomarkers of kidney tubule injury associate with incident hypertension in older adults with comorbidities, but less is known about these associations in younger adults.. In 1170 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults; mean age, 45 years; 40% Black people; 56% women) without hypertension, cardiovascular disease, or kidney disease at baseline, we examined associations of urine MCP-1 (monocyte chemoattractant protein-1), α1m (alpha-1-microglobulin), KIM-1 (kidney injury molecule-1), EGF (epidermal growth factor), IL (interleukin)-18, YKL-40 (chitinase-3-like protein 1), and UMOD (uromodulin) with incident hypertension (onset of systolic blood pressure [BP] ≥130 mm Hg or diastolic BP ≥80 mm Hg or initiation of hypertension medications) and longitudinal BP change in models adjusted for hypertension risk factors, estimated glomerular filtration rate, and albuminuria.. After a median 9.9 (interquartile range, 5.9-10.2) years, 376 participants developed incident hypertension. In demographic-adjusted analyses, higher tertiles of EGF associated with lower risk of incident hypertension in both Black and White participants. After multivariable adjustment, the risk of incident hypertension remained lower in tertile 2 (hazard ratio, 0.70 [95% CI, 0.50-0.97]) and tertile 3 (hazard ratio, 0.58 [0.39-0.85]) of EGF versus tertile 1. In fully adjusted models, participants in EGF tertile 3 had smaller 10-year increases in systolic (-3.4 [95% CI, -6.1 to -0.7] mm Hg) and diastolic BP (-2.6 [95% CI, -4.6 to -0.6] mm Hg) than tertile 1. Other biomarkers showed inconsistent associations with incident hypertension and BP change.. In middle-aged adults without hypertension, cardiovascular disease, or kidney disease, higher urine EGF associated with lower risk of incident hypertension and lower 10-year BP elevations.

Topics: Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Hypertension; Hypotension; Kidney Diseases; Kidney Tubules; Male; Middle Aged; Risk Factors; Young Adult

To evaluate the role of urinary Monocyte Chemotactic Protein-1 (MCP1) and urinary epidermal growth factor (EGF) in diagnosing of upper urinary tract obstruction (UUTO).. Over a period of 6 months (January 2022 to June 2022) this prospective case control comparative study was conducted on 120 participants, 60 of them with UUTO and 60 healthy controls. A morning urine sample of all participants was tested for EGF and MCP-1. after taking a detailed history taking and laboratory and radiological evaluation.. Urinary MCP-1(uMCP-1) was significantly (p-value = 0.000) increased in UUTO group showing a mean ± SD of 518.10 ± 51.19 ng/L compared to a mean ± SD of 143.32 ± 58.03 ng/L in the controls, whereas a significantly (p-value = 0.000) decrease of urinary EGF (uEGF) was observed in patients with UUTO compared to control group. A significant difference of uEGF level and uEGF/uMCP1 ratio was observed between mild compared to moderate/severe UUTO.. Utilization of the urinary biomarker MCP1, EGF and uEGF/uMCP1 ratio in patients with UUTO can adequately be used as a simple, efficacious and noninvasive way in diagnosis of UUTO.

Topics: Biomarkers; Chemokine CCL2; Epidermal Growth Factor; Humans; Kidney; Kidney Diseases

The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age.. Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%,. Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.

Topics: Albuminuria; Animals; Biomarkers; Cytokines; Disease Models, Animal; Early Diagnosis; Epidermal Growth Factor; Hypertriglyceridemia; Inflammation Mediators; Kidney Diseases; Lipids; Male; Metabolic Syndrome; Predictive Value of Tests; Proteomics; Rats, Transgenic; Rats, Wistar; Time Factors; Urinalysis

Urinary levels of EGF may be a noninvasive biomarker of the degree of interstitial fibrosis. However, all the available data are based on studies that examined the EGF/creatinine ratio in spot urine samples. The agreement between EGF/creatinine ratio and 24-hours EGF excretion has not been analyzed, neither has it been established which of these two measurements is a better predictor of the degree of interstitial fibrosis. To investigate whether the EGF/creatinine ratio can predict 24-hours EGF, and which of these two measures is a better predictor of interstitial fibrosis in patients with IgA nephropathy (IgAN).. This is a cross-sectional study including 80 patients with IgAN. EGF levels were measured by ELISA in spot second-morning and 24-hours urine samples. We analyzed the concordance between these two measures and their respective ability to predict interstitial kidney fibrosis.. The intraclass correlation coefficient between 24-hours and spot EGF/creatinine was 0.63 (95% CI: 0.54 - 0.70), bias was 2.7 µg/mL (95% CI: 2.1 - 7.5). Passing-Bablok regression did not show a significant deviation from linearity (p = 0.72). Bland-Altman showed a systematic and proportional error between both EGF measures. Spot EGF/creatinine ratios overestimated the 24-hours EGF at low excretion values and underestimated it at high excretion values. In univariate analyses, 24-hours excretion of EGF was a better predictor of interstitial fibrosis than spot EGF/creatinine ratio (R2: 0.43 vs. 0.30, p = 0.000). In multivariate analyses, the 24-hours excretion of EGF plus GFR, significantly improved the prediction of interstitial fibrosis when compared with GFR alone (R2: 0.52 vs. 0.39, p = 0.000). When spot-urine EGF was introduced instead of the 24-hours excretion, the model was statistically significant but had a lower predictive capacity (R2: 0.46 spot EGF/creatinine vs. R2: 0.52 24-hours EGF excretion, p = 0.000).. The 24-hours excretion of EGF should be considered as the first-choice measure to estimate the interstitial fibrosis. The EGF/creatinine ratio cannot accurately estimate the total EGF excretion of but it also improves the estimation of the fibrosis surface, and, consequently, could be an alternative whenever 24-hours urine samples cannot be obtained.

Topics: Adult; Aged; Biomarkers; Creatinine; Cross-Sectional Studies; Epidermal Growth Factor; Female; Fibrosis; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests; Sensitivity and Specificity

Recovery from ischemic acute kidney injury requires the replacement of damaged tubular cells. This repair process involves epidermal growth factor (EGF) synthesized in medullary the thick ascending limbs (mTAL) of Henle. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, increases glomerular filtration rate and renal medullary blood flow. However, the effects of ANP on renal recovery after I/R-induced renal injury remain unclear. We therefore examined whether human ANP enhances recovery from I/R-induced renal injury by reducing damage to EGF-producing kidney cells in a rat model. Male Wistar rats weighing 200-240 g were observed for 48 h after reperfusion following 45-min renal ischemia. Rats were intravenously administered alpha-human ANP (alpha-hANP) at 0.2 microg/kg/min beginning immediately after ischemia and continuing for 2 h after reperfusion. Outer medullary blood flow (OMBF), EGF mRNA, serum blood urea nitrogen (BUN) and creatinine levels as indicators of glomerular function were measured, while urinary N-acetyl beta-D-glucosaminidase (NAG) was used as a specific indicator of proximal tubular function. OMBF was increased by alpha-hANP after reperfusion and maintained significantly higher mRNA level of EGF in the kidney 24 h after reperfusion. I/R-induced increases in serum concentrations of BUN and creatinine and urinary concentrations of NAG were also reduced by alpha-hANP, with improved histopathological changes, including acute tubular necrosis at 24-48 h after reperfusion. This report is the first to demonstrate that alpha-hANP accelerates recovery following renal ischemic insult by reducing the damage to EGF-producing kidney cells.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Blood Urea Nitrogen; Creatinine; Epidermal Growth Factor; Humans; Kidney; Kidney Diseases; Male; Rats; Rats, Wistar; Renal Circulation; Reperfusion Injury; Urea

Proteinuria, inflammation, chronic hypoxia, and rarefaction of peritubular capillaries contribute to the progression of renal disease by affecting proximal tubular epithelial cells (PTECs). To study the transcriptional response that separates patients with a stable course from those with a progressive course of disease, we isolated PTECs by laser capture microdissection from cryocut tissue sections of patients with proteinuric glomerulopathies (stable n=20, progressive n=11) with a median clinical follow-up of 26 months. Gene-expression profiling and a systems biology analysis identified activation of intracellular vascular endothelial growth factor (VEGF) signaling and hypoxia response pathways in progressive patients, which was associated with upregulation of hypoxia-inducible-factor (HIF)-1alpha and several HIF target genes, such as transferrin, transferrin-receptor, p21, and VEGF-receptor 1, but downregulation of VEGF-A. The inverse expression levels of HIF-1alpha and VEGF-A were significantly superior in predicting clinical outcome as compared with proteinuria, renal function, and degree of tubular atrophy and interstitial fibrosis at the time of biopsy. Interactome analysis showed the association of attenuated VEGF-A expression with the downregulation of genes that usually stimulate VEGF-A expression, such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and HIF-2alpha. In vitro experiments confirmed the positive regulatory effect of EGF and IGF-1 on VEGF-A transcription in human proximal tubular cells. Thus, in progressive but not in stable proteinuric kidney disease, human PTECs show an attenuated VEGF-A expression despite an activation of intracellular hypoxia response and VEGF signaling pathways, which might be due to a reduced expression of positive coregulators, such as EGF and IGF-1.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Cohort Studies; Epidermal Growth Factor; Epithelial Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Tubules, Proximal; Microdissection; Oligonucleotide Array Sequence Analysis; p21-Activated Kinases; Signal Transduction; Vascular Endothelial Growth Factor A

Chronic renal disease is characterized by declining renal function, loss of intrinsic renal cells, and their replacement with fibrotic tissue. This study investigates apoptosis and its regulation in the context of chronic renal disease. RNA was extracted from renal biopsies from patients with various forms of chronic renal disease. Expression of genes of the Bcl-2 family, death receptor pathway, and growth factors were measured by reverse-transcription real-time polymerase chain reaction. Apoptosis was detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling technique. Tubulointerstitial apoptosis was positively associated with tubulointerstitial injury and renal dysfunction and increased 2.3-fold per unit (U) increase in transforming growth factor beta(1) (TGFbeta(1)) mRNA (P<0.05). Conversely, a 1 U increase in epidermal growth factor (EGF) mRNA was associated with a 47% decrease in tubulointerstitial apoptosis (P<0.05). Tubulointerstitial injury was correlated with increased TGFbeta(1) and tumour necrosis factor alpha (TNFalpha) mRNA (P<0.005) and decreased EGF mRNA (P<0.05). Additionally, for a 10 U decrease in the glomerular filtration rate there was an estimated increase of 5 and 10% in TGFbeta(1) and TNFalpha mRNA, respectively (P<0.05), whereas EGF mRNA decreased by an estimated 15% (P<0.005). Therefore dysregulation of cytokine/growth factor expression plays a central role in the progression of chronic renal disease through contribution to renal cell loss, tubulointerstitial injury, and renal dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers; Biopsy; Chronic Disease; Epidermal Growth Factor; Female; Gene Expression; Gene Expression Regulation; Glomerular Filtration Rate; Humans; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Kidney Tubules; Male; Middle Aged; Proteinuria; RNA, Messenger; Transforming Growth Factor beta1; Treatment Outcome; Tumor Necrosis Factor-alpha

To examine whether the reversibility of chronic cyclosporine A (CsA) nephrotoxicity is associated with apoptotic cell death and its regulatory factors.. Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administering CsA (15 mg/kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay and the expression of pro-apoptotic [transforming growth factor-beta 1 (TGF-beta 1) and Fas] and anti-apoptotic [epidermal growth factors (EGF) and Bcl-2] factors.. Discontinuation of CsA induced significant decreases in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells was correlated with the tubulointerstitial fibrosis score (r=0.919, P<0.01). Upregulation of TGF-beta and Fas expression in CsA-treated rat kidneys was decreased significantly after withdrawal of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels.. CsA withdrawal is associated with a decrease in apoptotic cell death and with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity.

Topics: Animals; Apoptosis; Cyclosporine; Epidermal Growth Factor; Fas Ligand Protein; Kidney; Kidney Diseases; Male; Membrane Glycoproteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substance Withdrawal Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1

Reflux nephropathy (RN) is recognised as a major cause of end stage renal failure in children and young adults. The histological findings of RN are tubular atrophy and interstitial monocyte infiltration. Epidermal growth factor (EGF) produced by tubular cells playing a pivotal role in the modulation of tubular cell growth, while monocyte chemotactic peptide-1 (MCP-1) is a powerful and specific chemotactic and activating factor for monocytes. It has been suggested that the modulation of local EGF production is directly involved in the pathogenesis of tubular damage. We designed this study to investigate the expression of EGF and MCP-1 in severe reflux nephropathy in order to further understand the pathogenesis of reflux nephropathy.. The kidney specimens from 12 children with severe reflux nephropathy were obtained at the time of nephrectomy. Control material included normal kidney specimens obtained from three adult patients during partial nephrectomy for an incidentaloma. Single-label immunofluorescence histochemistry was carried out using polyclonal antibodies to EGF and MCP-1 employing laser scanning confocal microscopy. EGF and MCP-1 gene expression were evaluated by in situ hybridization (ISH). TUNEL method was utilized to assess tubular apoptosis.. In the normal kidney there was strong EGF immunoreactivity in the proximal tubules compared to the reflux nephropathy where there was lack of immunoreactivity in the proximal tubules. Normal kidney demonstrated lack of MCP-1 immunoreactivity, whereas reflux nephropathy kidney showed strong MCP-1 immunoreactivity in the proximal tubules and tubulointerstitial space. In the normal kidney there was marked EGF mRNA expression in the proximal tubules whereas EGF mRNA expression was undetectable in reflux nephropathy kidney. MCP-1 mRNA expression was undetectable in normal kidney, whereas there was strong MCP-1 mRNA expression at the tubulointerstitial level in reflux nephropathy kidney. Decreased EGF expression and increased MCP-1 expression at the tubulointerstitial levels in reflux nephropathy strongly correlated with severity of apoptosis in reflux nephropathy compared with controls.. Our data suggests that the downregulation of EGF with simultaneous upregulation of MCP-1 may be involved in the pathogenesis of tubulointerstitial damage in reflux nephropathy.

Topics: Adolescent; Biomarkers; Case-Control Studies; Chemokine CCL2; Child; Child, Preschool; Culture Techniques; Down-Regulation; Epidermal Growth Factor; Female; Humans; Immunohistochemistry; In Situ Hybridization; In Situ Nick-End Labeling; Infant; Kidney Diseases; Male; Nephrectomy; Probability; Prognosis; RNA, Messenger; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric; Up-Regulation; Vesico-Ureteral Reflux

The AP-1 transcription factor, composed of Jun and Fos proteins, plays a crucial role in the fine tuning of cell proliferation. We showed previously that AP-1 complexes are activated during the proliferative response that parallels the development of renal lesions after nephron reduction, but little is known about the specific role of individual Jun/Fos components in the deterioration process. Here we used JunD knockout (JunD-/-) mice and an experimental model of chronic renal injury (75% nephron reduction) to explore the role of JunD. Nephron reduction resulted in an initial compensatory growth phase that did not require JunD. JunD, however, was essential to inhibit a second wave of cell proliferation and to halt the development of severe glomerular sclerosis, tubular dilation, and interstitial fibrosis. We show that the effects of junD inactivation are not cell autonomous and involve upregulation of the paracrine mitogen, TGF-alpha. Expression of a transgene (REM) encoding a dominant negative isoform of the EGFR, the receptor for TGF-alpha, prevented the second wave of cell proliferation and the development of renal lesions in bitransgenic JunD-/-/REM mice. We propose that JunD is part of a regulatory network that controls proliferation to prevent pathological progression in chronic renal diseases.

Topics: Animals; Cell Division; Chronic Disease; Epidermal Growth Factor; ErbB Receptors; Humans; Kidney; Kidney Diseases; Mice; Mice, Knockout; Mitogens; Paracrine Communication; Proto-Oncogene Proteins c-jun; Signal Transduction; Transcription Factor AP-1; Transforming Growth Factor alpha; Up-Regulation

We studied control of the epidermal growth factor (EGF) receptor and its ligands during kidney injury, since they may be importantly involved in repair.. The folic acid model of renal injury was used in these studies. Messenger RNA (mRNA) was evaluated by solution hybridization. Immunohistochemistry of transforming growth factor alpha (TGF-alpha) was also performed.. Twenty-four hours after folic acid induced acute renal injury, creatinine increased from 0.3 +/- 0.03 mg/dl in controls to 2.0 +/- 0.8 mg/dl in folic acid injured kidneys (n = 4, p < 0.03). mRNA for the EGF receptor was increased nearly sevenfold by 24 h, and mRNA for the receptor was increased as early as 1 h following folic acid treatment. EGF receptor ligand caused a profound downregulation of the receptors in proximal tubule basolateral membranes, but receptors returned rapidly to the membrane surface in injured kidneys. The mRNA levels for heparin-binding EGF and TGF-alpha, two EGF receptor ligands, increased within 1 h of injury. TGF-alpha mRNA increased from 1.0 +/- 0.09 (relative densitometry units) in control animals to 2.9 +/- 0.13 in folic acid treated rats at 24 h (n = 4, p < 0.01), and immunohistochemical staining for TGF-alpha increased in injured kidneys at distal nephron sites.. These studies indicate that upregulation of the EGF receptor is related to an increase in mRNA. The rapid return of receptors to the membrane surface following ligand stimulation may be useful in maintaining a mitogenic stimulus. Multiple EGF-like ligands may be important in activating the upregulated EGF receptor during repair from renal injury.

Topics: Acute Disease; Animals; Creatinine; Epidermal Growth Factor; ErbB Receptors; Folic Acid; Gene Expression; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Ischemia; Kidney Diseases; Ligands; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor alpha

Topics: Animals; Animals, Genetically Modified; Chronic Disease; Disease Progression; Epidermal Growth Factor; ErbB Receptors; Growth Substances; Humans; Ischemia; Kidney Diseases; Kidney Tubules; Nephrectomy

This study examined the repair of renal proximal tubule cellular (RPTC) functions following sublethal injury induced by the nephrotoxicant S-(1,2-dichlorovinyl)-L-cysteine (DCVC). DCVC exposure resulted in 31% cell death and loss 24 h following the treatment. Monolayer confluence recovered through migration/spreading but not proliferation after 6 days. Basal, uncoupled, and ouabain-sensitive oxygen consumption (QO2) decreased 47, 76, and 62%, respectively, 24 h after DCVC exposure. Na+-K+-ATPase activity and Na+-dependent glucose uptake were inhibited 80 and 68%, respectively, 24 h after DCVC exposure. None of these functions recovered over time. Addition of epidermal growth factor (EGF) following DCVC exposure did not prevent decreases in basal, uncoupled, and ouabain-sensitive QO2 values and Na+-K+-ATPase activity but promoted their recovery over 4-6 days. In contrast, no recovery of Na+-dependent glucose uptake occurred in the presence of EGF. These data show that: 1) DCVC exposure decreases mitochondrial function, Na+-K+-ATPase activity, active Na+ transport, and Na+-dependent glucose uptake in sublethally injured RPTC; 2) DCVC-treated RPTC do not proliferate nor regain their physiological functions in this model; and 3) EGF promotes recovery of mitochondrial function and active Na+ transport but not Na+-dependent glucose uptake. These results suggest that cysteine conjugates may cause renal dysfunction, in part, by decreasing RPTC functions and inhibiting their repair.

Topics: Animals; Cell Division; Cysteine; Epidermal Growth Factor; Female; Intracellular Membranes; Kidney Diseases; Kidney Tubules, Proximal; Microvilli; Mitochondria; Oxygen Consumption; Rabbits; Regeneration; Wound Healing

Inhibition of angiotensin action, pharmacologically or genetically, during the neonatal period leads to renal anomalies involving hypoplastic papilla and dilated calyx. Recently, we documented that angiotensinogen (Agt -/-) or angiotensin type 1 receptor nullizygotes (Agtr1 -/-) do not develop renal pelvis nor ureteral peristaltic movement, both of which are essential for isolating the kidney from the high downstream ureteral pressure. We therefore examined whether these renal anomalies could be characterized as "obstructive" nephropathy.. Agtr1 -/- neonatal mice were compared with wild-type neonates, the latter subjected to surgical complete unilateral ureteral ligation (UUO), by analyzing morphometrical, immunohistochemical, and molecular indices. Agtr1 -/- mice were also subjected to a complete UUO and were compared with wild-type UUO mice by quantitative analysis. To assess the function of the urinary tract, baseline pelvic and ureteral pressures were measured.. The structural anomalies were qualitatively indistinguishable between the Agtr1 -/- without surgical obstruction versus the wild type with complete UUO. Thus, in both kidneys, the calyx was enlarged, whereas the papilla was atrophic; tubulointerstitial cells underwent proliferation and also apoptosis. Both were also characterized by interstitial macrophage infiltration and fibrosis, and within the local lesion, transforming growth factor-beta 1, platelet-derived growth factor-A and insulin-like growth factor-1 were up-regulated, whereas epidermal growth factor was down-regulated. Moreover, quantitative differences that exist between mutant kidneys without surgical obstruction and wild-type kidneys with surgical UUO were abolished when both underwent the same complete surgical UUO. The hydraulic baseline pressure was always lower in the pelvis than that in the ureter in the wild type, whereas this pressure gradient was reversed in the mutant.. The abnormal kidney structure that develops in neonates during angiotensin inhibition is attributed largely to "functional obstruction" of the urinary tract caused by the defective development of peristaltic machinery.

Topics: Actins; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Animals, Newborn; Apoptosis; Cell Division; Disease Models, Animal; Epidermal Growth Factor; Gene Expression Regulation, Developmental; In Situ Hybridization; In Situ Nick-End Labeling; Insulin-Like Growth Factor I; Kidney Diseases; Kidney Medulla; Kidney Pelvis; Macrophages; Mice; Mice, Knockout; Muscle, Smooth; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Pressure; RNA, Messenger; Transforming Growth Factor beta; Ureter; Ureteral Obstruction

Topics: Acetylglucosaminidase; Adult; Antigens, CD; Biomarkers; Child; Child, Preschool; Cytokines; Epidermal Growth Factor; Humans; Kidney Diseases; Proteins; Vesico-Ureteral Reflux

To examine at a molecular level the repair process during recovery from acute renal failure, we determined, after nephrotoxic acute renal injury, levels for several RNAs associated with differentiated functions in the kidney. To delineate changes in different regions, we determined RNA levels separately in cortex, outer medulla, and inner medulla of adult rat kidney. Several RNAs were regionally distributed in control kidneys, including epidermal growth factor (EGF, highest in cortex and outer medulla), aldose reductase (highest in inner medulla), and prostaglandin synthase (highest in inner medulla). Futhermore, RNA for the heat shock protein Hsp70 was present at high levels in the inner medulla of controls. A single intraperitoneal dose of folic acid caused reversible, nonoliguric acute renal failure with impairment of glomerular filtration, tubular sodium reabsorption, and urinary concentration. Fractional excretion of sodium returned to normal by day 3, while serum creatinine, serum urea nitrogen, and urinary osmolality remained abnormal until day 7. During acute renal failure there was a marked, reversible decrease in the regional mRNA levels for EGF, aldose reductase, prostaglandin synthase, and Hsp70. Aldose reductase, prostaglandin synthase, and Hsp70 RNA levels returned to control levels by 7 to 10 days, while EGF remained depressed for a more prolonged period. High levels of aldose reductase, prostaglandin synthase, and Hsp70 RNAs in the inner medulla and their loss/recovery during acute renal failure with a time course similar to alterations in urinary osmolality were consistent with regulation in response to changes in inner medullary osmolality, as has been demonstrated for aldose reductase in normal animals. (ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Aldehyde Reductase; Animals; Epidermal Growth Factor; Folic Acid; Gene Expression; HSP70 Heat-Shock Proteins; Kidney Diseases; Kidney Medulla; Kinetics; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; RNA; RNA, Messenger

To examine the excretion of urinary epidermal growth factor (EGF) in urological diseases and the relationship of EGF urine levels with transitional cell carcinoma (TCC), we measured the concentration of EGF by radioimmunoassay. The series comprised patients with active TCC (n = 52), others in tumor-free status (n = 29) and with non-neoplastic inflammatory diseases (n = 43), and normal controls (n = 50). Urinary EGF values were lower in patients with urological diseases of different etiologies than in normal controls (P < 0.005). Mean EGF levels of patients who had previous bladder tumor resection (n = 21) were not statistically different from normal controls (P = 0.2). For patients with active TCC, EGF urine levels showed a significant inverse relationship to increasing tumor grade (P = 0.02). In addition, subjects who had received nephrectomy for pelvic carcinoma (n = 8) showed significantly lower mean EGF values than those with intact kidneys (n = 21), irrespective of sex (P < 0.05). Immunostaining of EGF on non-neoplastic kidney (n = 9) revealed reactivity in the distal convoluted tubules and thick ascending limbs of Henle. Our results suggest that the kidney is the major source of urinary EGF. Its excretion in urine is decreased in both inflammatory and neoplastic diseases of the urinary tract. EGF may play an important part in the biological activity of TCC. Further study is indicated to investigate the monitoring of EGF urine levels as a marker of recurrence for EGF receptor-positive TCC.

Topics: Adult; Aged; Aged, 80 and over; Cystitis; Epidermal Growth Factor; Female; Humans; Kidney Diseases; Male; Middle Aged; Pyelonephritis; Urinary Bladder Diseases

Epidermal growth factor (EGF) is a potent mitogen for renal tubular cells that possess specific high-affinity binding sites for this polypeptide. However, actual function of EGF within the kidney remains to be elucidated. We evaluated the effect of exogenous EGF administration on the rate of tubular regeneration in an experimental model of gentamicin (GT) nephrotoxicity. Female Sprague-Dawley rats were anesthetized, and a miniosmotic pump filled with mouse EGF or saline was implanted subcutaneously. Twenty-four hours later, GT (40 mg.kg-1 x 12 h-1 ip) was given for 4 and 8 days. Groups of treated animals and controls were killed either the day after cessation of treatment (days 5 and 9) or 4 and 8 days after the end of 8-day GT administration (days 12 and 16). Cortical GT levels of groups killed at days 5, 9, 12, and 16 were similar in animals infused with saline or EGF. Serum creatinine levels were significantly higher in GT-treated animals infused with EGF or saline and killed at days 9 and 12 compared with saline-treated animals infused with EGF or saline alone (P < 0.01). Blood urea nitrogen (BUN) also increased as a result of GT administration. However, in animals receiving GT and EGF and killed at day 16, mean BUN level was significantly lower (P < 0.01) compared with rats dosed with GT alone. In treated rats, the extent of tubular regeneration, evaluated by the rate of [3H]thymidine incorporation into renal cortical DNA or by the frequency of S-phase cells (histoautoradiography), was increased in a dose- and time-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Division; DNA; Epidermal Growth Factor; Female; Gentamicins; Kidney; Kidney Cortex; Kidney Diseases; Necrosis; Rats; Rats, Sprague-Dawley; Time Factors

The roles of growth factors in the pathogenesis of various forms of acute and chronic renal disease are largely putative. Nevertheless, there is a growing body of information that links specific growth factors to particular forms of renal injury. In all instances, it is supposed that such associations are not necessarily unique and that multiple cytokines probably interact to determine the pattern of injury or the regenerative response to such injury. Regeneration of tubular epithelium after acute tubular necrosis involves upregulation of the epidermal growth factor (EGF) receptor. Early studies of exogenously administered EGF indicate that the severity and duration of renal failure may be attenuated by this growth factor. Thus far, the observed responses have been limited and the role of EGF as a therapeutic agent requires more study. The mechanism of generation of tubulointerstitial injury in most forms of renal disease is difficult to understand. Early in vitro studies of growth factor production by tubular cells (in the absence of any infiltrating cells) indicate that platelet-derived growth factor produced by the medullary collecting duct is mitogenic for renal medullary fibroblasts, suggesting a paracrine growth system in this region of the kidney. Insulin-like growth factor I has also been shown to be produced by collecting duct cells. Its production is increased by EGF, and its association with certain forms of renal hypertrophy, i.e., diabetes and hypersomatotrophic states, implies its participation in the hypertrophic growth response. Platelet-derived growth factor is a potent mitogen for glomerular mesangial cells, and its production is regulated by a variety of cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Division; Epidermal Growth Factor; Fibrosis; Glomerular Mesangium; Growth Substances; Humans; Hypertrophy; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrectomy; Platelet-Derived Growth Factor; Rats; Regeneration; Transforming Growth Factor beta

We have previously demonstrated that changes in urinary epidermal growth factor/creatinine ratios relate to gestational age and gender. It is unclear what controls this developmental pattern although chronic renal disease and thyroid aberrations have significant effects on epidermal growth factor and creatinine excretion in childhood and in adults. Therefore, we chose to explore the effects of these disease states on epidermal growth factor excretion during the perinatal time period. We collected urine samples from 8 infants with congenital renal disease and 45 infants with low T4 and normal TSH values who 'failed' the newborn screen. In addition, 2 infants with hypothyroidism and 2 infants with neonatal Grave's disease had urine samples examined. Values were compared with the epidermal growth factor and creatinine excretion from 190 infants. We demonstrated that epidermal growth factor excretion increased earlier in gestation than does creatinine excretion. In infants with renal disease or hypothyroidism, epidermal growth factor excretion was decreased while hyperthyroidism enhanced excretion. Epidermal growth factor excretion increased with relief of an obstruction but still remained low and creatinine excretion was unchanged. We confirm that in preterm infants as in childhood there are similar effects of thyroid and renal diseases on epidermal growth factor excretion.

Topics: Congenital Hypothyroidism; Creatinine; Epidermal Growth Factor; Female; Humans; Hydronephrosis; Hyperthyroidism; Hypothyroidism; Infant; Infant, Newborn; Kidney; Kidney Diseases; Male

In this study we describe the occurrence of a calmodulin-like protein in normal human biological fluids. Extraction of the calmodulin-like protein from breast milk, saliva, serum and urine provided an extract with enhanced calmodulin immunoreactivity which, in the case of milk and saliva, showed a protein band comigrating with authentic calmodulin (Mr 17,000) on sodium dodecylsulphate-polyacrylamide gel electrophoresis. However, in milk, saliva and serum a major protein band of Mr 14,000-15,000 was always observed, which we speculate may be related to calmodulin, possibly as a partially degraded form. Estimates of biologically active calmodulin in most normal extracellular fluids were of the order which we have found will stimulate cell division when added to the extracellular medium of cells in culture. Levels ranged from 0.03 nmol/l in urine to 18.6 nmol/l in breast milk, and exhibited a quantitative relationship (r = 0.79, P less than 0.01) to epidermal growth factor (EGF) levels in fluids. Where EGF concentrations varied from normal (increased in saliva 24 h after oral surgery and reduced in the urine of patients with renal failure) calmodulin concentrations were similarly affected. The presence of calmodulin in serum may in part be attributable to its release from platelets which are particularly rich in calmodulin. Release of calmodulin from the platelet was associated with that of EGF and other platelet products.

Topics: Blood Platelets; Body Fluids; Calmodulin; Epidermal Growth Factor; Extracellular Space; Female; Humans; Kidney Diseases; Male; Mouth; Radioimmunoassay; Serotonin

In order to investigate the contribution of growth factors in conditions of postoperative stress, we measured the blood and urine hEGF levels in patients with various surgical disorders. While the levels of serum and plasma hEGF did not change significantly after surgery, urine hEGF (u-hEGF) stayed at the base-level followed by a single peak within a postoperative period of two weeks. The peak day of u-hEGF in patients with more than 1000 ml of intraoperative bleeding was later than that in patients with bleeding of less than 1000 ml. In patients with postoperative renal failure or dysfunction, u-hEGF levels dropped and did not rise until the recovery of renal function. The changing pattern of u-hEGF levels was an indicator of operative bleeding volume and renal function.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Epidermal Growth Factor; Female; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Middle Aged; Surgical Procedures, Operative; Time Factors

We determined the concentrations of immunoreactive epidermal growth factor (irEGF) and creatinine in urine samples from 47 adult patients with various kidney diseases and wide ranges of azotemia and proteinuria. In most of the patients, urinary irEGF concentrations (nanograms per mg creatinine) were markedly subnormal. In the entire group, urinary irEGF correlated with creatinine clearance (r = 0.79; P less than 0.001) and serum creatinine concentration (r = -0.85; P less than 0.001). In the subgroups of patients with primarily glomerular or tubulointerstitial diseases, similar correlations were found. By contrast, there was no correlation with proteinuria. We also determined the concentrations of plasma irEGF in five patients with azotemia. In four patients, the irEGF to creatinine concentration ratio was 1.9- to 8.9-fold higher in urine than in plasma, indicating that plasma irEGF was not the main source of urinary irEGF in these patients. Our data are compatible with the theory that urinary irEGF originates from nephrons per se.

Topics: Adolescent; Adult; Aged; Creatine; Epidermal Growth Factor; Female; Humans; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged; Radioimmunoassay

Epidermal growth factor (EGF)/urogstrone is a polypeptide hormone that stimulates growth of a variety of tissues and inhibits gastric acid secretion. Although it was originally isolated from male mouse submaxillary glands, EGF/urogastrone has recently been isolated from human urine. We detected EGF-like activity in human urine, milk and saliva by radioreceptor assay using the male mouse hepatic microsomal fraction as a receptor preparation and mouse EGF as reference standard. On Sephadex G-50 gel chromatography, major EGF-like activity (RRA-EGF) in human urine, milk and saliva was eluted near the portion where standard mouse EGF was eluted (Kav = 0.5, MW approximately equal to 6000). Isoelectric focusing revealed that isoelectric point of major RRA-EGF was 4.45 with minor heterogeneity. Twenty-four hour urinary excretion of RRA-EGF in adult males and females with normal renal function was 88.8 +/- 4.0 and 65.2 +/- 7.9 (mean +/- SE) microgram/total volume or 141 +/- 7.2 and 96.5 ng/mg of creatinine, respectively. There was no apparent diurnal rhythm in urinary RRA-EGF excretion. A series of 24 h urine collection over 5 days from adults showed relatively small variations. Urinary levels of EGF per mg creatinine in normal children were significantly higher than those in normal males or females. There was a reverse correlation between serum creatinine levels and urinary EGF levels per creatinine. The concentration of RRA-EGF in human milk collected 7 days after starting breast feeding was 81 +/- 11 ng/ml. The salivary RRA-EGF concentration was 6.5 +/- 1.0 and 6.9 +/- 0.3 in normal adult males and females, respectively.

Topics: Adult; Animals; Body Fluids; Child; Child, Preschool; Chromatography, Gel; Circadian Rhythm; Creatinine; Epidermal Growth Factor; Female; Humans; Infant; Kidney Diseases; Male; Middle Aged; Milk; Radioligand Assay; Saliva; Sex Factors