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Biomedical subjects

R Hirschberg

Publications and source records attributed to R Hirschberg.

At least 19 recordsLinked to original sources
PubMed2001

Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy.

BACKGROUND: Chronic interstitial fibrosis, which follows the onset of glomerular proteinuria, importantly contributes to progressive renal failure in diabetic nephropathy. The present studies examine the potential role of tubular connective tissue growth factor (CTGF). METHODS: The expression of CTGF was examined in rats with diabetic nephropathy. Regulation and actions of CTGF were studied in in vitro cell culture models. RESULTS: CTGF mRNA levels were increased in the renal cortex of rats with streptozotocin-induced diabetes compared with controls. Immunohistology indicated that CTGF was expressed in renal cortex of diabetic rats, in contrast to controls in some tubular cross-sections, particularly dilated-appearing proximal tubules, in which it tended to colocalize with insulin-like growth factor-I (IGF-I). Glomerular ultrafiltrate from diabetic rats, which contained bioactive transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF), induced increased CTGF expression in tubular cells. TGF-beta1 and, to a lesser extent, HGF also raised CTGF expression in cultured proximal tubular cells. In contrast, high glucose (25 mmol/L) did not increase the secretion of CTGF. In cultured tubular cells, rhCTGF moderately increased fibronectin but not collagen (Col) type I and type III expression. In NRK-49F renal interstitial fibroblasts, CTGF raised Col alpha1III and thrombospondin-1 levels. CTGF has an IGF-binding domain and binds to IGF-I. In NRK-49F cells, IGF-I increased the activity of CTGF towards the expression of Col alpha1III. CONCLUSIONS: CTGF is expressed and regulated downstream from TGF-beta and HGF in proximal tubular cells, is induced by diabetic rat glomerular ultrafiltrate, and has moderate profibrogenic activity in tubular cells and renal interstitial fibroblasts, where its activity is IGF-I dependent. By these means, CTGF may act downstream of TGF-beta and HGF and may contribute to chronic tubulointerstitial fibrosis in diabetic nephropathy.

Animals↗
PubMed2000

Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy.

BACKGROUND: The present in vivo and in vivo experiments were performed to test the hypothesis that in rats with glomerular proteinuria, the bioactive growth factors transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) are ultrafiltered into tubular fluid, can interact with respective receptors in apical tubular cell membranes, increase the expression and basolateral secretion of C-C-chemokines, which interact with cells in the renal interstitium and indirectly cause myofibroblasts to increase the expression of extracellular matrix proteins. METHODS: HGF and TGF-beta were measured by Western blot and bioassay in glomerular ultrafiltrate that was collected by nephron micropuncture from rats with diabetic nephropathy and control rats. Proximal tubular and collecting duct cells were incubated with diluted proximal tubular fluid or recombinant human HGF (rhHGF) or rhTGF-beta and expression of C-C-chemokines was measured by RT-PCR and ELISA. Interactions of tubular cell chemokines with macrophages and indirectly with myofibroblasts were also examined using cell culture models. RESULTS: In rats with glomerular proteinuria due to diabetic nephropathy mature, bioactive HGF as well as active and latent TGF-beta were detected in early proximal tubular fluid. Specific HGF- and TGF-beta type II receptors were expressed in apical tubular membranes more in diabetic compared to control rats. Incubation of cultured mouse proximal tubular cells (mPTC) or medullary collecting duct cells (mIMCD-3) with diabetic rat proximal tubular fluid increased MCP-1 and RANTES mRNA levels as well as secreted peptide up to threefold. In contrast, high glucose (450 mg/dL), bovine serum albumin (BSA) or rat albumin (each at 100 micrograms/mL) or 10 nmol/L insulin-like growth factor-I (IGF-I; which was also present in glomerular ultrafiltrate in rats with diabetic nephropathy) did not affect expression of these chemokines. Recombinant human TGF-beta as well as rhHGF each increased MCP-1 and RANTES mRNA as well as peptide levels several-fold. In cultured macrophages MCP-1 raised the secretion of TGF-beta, which in turn increased the expression of collagen type I and III as well as fibronectin in renal interstitial myofibroblasts about 2.5 to 4-fold. CONCLUSIONS: Proteinuria-induced progressive renal interstitial fibrosis may be caused by glomerular ultrafiltration of high molecular weight bioactive growth factors, HGF and TGF-beta, which "activate" tubular cells through apical membranes. These apical signals are translated into basolateral events that are recognized by cells in the interstitium, such as the basolateral secretion of the C-C-chemokines MCP-1 and RANTES, which may (via macrophages) stimulate interstitial myofibroblasts, and thus lead to accumulation of extracellular matrix proteins and progressive interstitial fibrosis.

Animals↗
PubMed2000

Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis.

Glomerular proteinuria is a risk factor for progression of chronic renal failure and contributes to renal interstitial fibrosis. In experimental diabetic glomerular sclerosis, there is translocation of high-molecular-weight growth factors, namely, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta, from plasma into tubular fluid, both of which act on tubular cells through apical membrane receptors. In the present studies, the hypothesis is examined that ultrafiltered HGF and TGF-beta induce increased expression of extracellular matrix (ECM) proteins directly in tubular cells, or induce increased expression of cytokines that may act on interstitial myofibroblasts. Incubation of cultured tubular cells with recombinant human (rh) TGF-beta modestly raises expression of collagen type III, but rhHGF dose dependently blocks expression of this ECM protein. Both growth factors raise fibronectin expression up to fourfold and increase expression of platelet-derived growth factor (PDGF)-BB up to sixfold, but not of fibroblast growth factor-2. Pooled, diluted glomerular ultrafiltrate that had been collected by nephron micropuncture from rats with diabetic nephropathy (24-30 wk) also raises expression of fibronectin as well as PDGF-BB in proximal tubular cells. In the presence of neutralizing antibodies that block actions of HGF and TGF-beta, diabetic rat glomerular ultrafiltrate fails to increase tubular cell PDGF-BB expression. In NRK-49F renal interstitial myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen type III but not type I or fibronectin. The findings provide evidence for ultrafiltered HGF and TGF-beta to contribute to interstitial accumulation of ECM proteins by direct effects on tubular cells as well as indirect mechanisms, via PDGF-BB and its action on myofibroblasts. These events may be important mechanisms of proteinuria-induced renal interstitial fibrosis and accelerated progression of chronic renal failure in diabetic nephropathy and perhaps other proteinuric glomerular diseases.

Animals↗
PubMed1999

Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy.

Insulin-like growth factor-I (IGF-I) is found in plasma at relatively high levels (approximately 40 nmol/L) but <1% is present in the free form and >99% is bound to specific binding proteins to form high-molecular-weight complexes of approximately 50 and approximately 150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-I-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-I receptors in apical tubular membranes. By this route, ultrafiltered IGF-I may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-I levels (227 +/- 34 ng/mL) were reduced as compared with control levels (319 +/- 33 ng/mL, P = .05), and IGF-binding protein-2 (IGFBP-2) is increased about 2-fold. In diabetic rats, IGF-I undergoes glomerular ultrafiltration and is present in proximal tubular fluid that was collected by nephron micropuncture at 2.54 +/- 0.54 nmol/L but is below the detection limit in tubular fluid from normal rats. IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 are all present in diabetic rat glomerular ultrafiltrate, but IGFBP-2 levels are greater than those of each of the other three IGFBPs. Neither recombinant human IGF-I (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-I and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of 22Na+ in distal tubule-like A6 cells through mechanisms involving apical IGF-I receptors. In normal rats, luminal infusion with rhIGF-I or with diabetic rat glomerular ultrafiltrate into late proximal tubules increases distal tubular Na+ absorption. These findings indicate that diabetic glomerular sclerosis causes glomerular ultrafiltration of IGF-I, and they suggest that tubular fluid IGF-I may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.

Animals↗
PubMed1999

Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.

BACKGROUND: Patients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism. METHODS: Our objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/- 1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12 hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to 14 days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate. RESULTS: During the treatment period, which averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days after the onset of treatment. CONCLUSIONS: rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity.

Acute Kidney Injury↗
PubMed1999

Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome.

In nephrotic glomerulopathies, there is ultrafiltration of high molecular weight forms of insulin-like growth factor-I (IGF-I), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-beta), which are bioactive in tubular fluid and act through apical tubular receptors. Experimental evidence indicates that ultrafiltered IGF-I, HGF, and TGF-beta may contribute to increased tubular phosphate and sodium absorption, synthesis of extracellular matrix proteins, and secretion of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Through these mechanisms, glomerular proteinuria may contribute to tubulointerstitial pathobiology in nephrotic syndrome.

Animals↗
PubMed1998

IGF-I binding proteins, IGF-I binding protein mRNA and IGF-I receptor mRNA in rats with acute renal failure given IGF-I.

BACKGROUND: Recombinant human insulin-like growth factor-I (rhIGF-I) accelerates recovery from acute renal failure (ARF) in rats. IGF-I acts through the IGF-I receptor (IGF-IR) and its actions may be modified by IGF-I binding proteins (IGFBPs). It therefore would be of value to determine the effects of both ARF and rhIGF-I treatment on serum IGFBPs and mRNA for IGFBPs and IGF-IR. METHODS: Rats with ARF and sham-operated control rats were randomized to receive rhIGF-I or vehicle injections thrice daily for 72 to 74 hours starting five hours after surgery. Serum IGFPBs 1 to 6 were measured serially, and mRNA for IGFBPs 1 to 6 and for IGF-IR were measured in several tissues obtained 72 to 74 hours after surgery. RESULTS: At 72 to 74 hours, serum IGFBP-1 and IGFBP-2 levels were higher in rhIGF-I treated rats. Serum IGFBP-3 was affected by both ARF and rhIGF-I. IGFBP-4 rose transiently only in ARF groups. At 72 to 74 hours, mRNA for several IGFBPs was reduced in renal cortex of ARF rats. Low mRNA for IGFBP-4 and -6 was observed in renal medulla of the ARF rats, particularly in comparison to the sham-operated rats receiving vehicle. Renal medullary IGFBP-2 mRNA was decreased in ARF and sham rats given rhIGF-I as compared to sham animals given vehicle. Hepatic IGFBP-2 mRNA was higher in both rhIGF-I treated groups versus those given vehicle. Otherwise, there were no differences in IGFBP mRNAs among the four groups in lung, heart, and skeletal muscle. IGF-IR mRNA was decreased in renal cortex and medulla of both ARF groups and was not detected in liver in any group. CONCLUSIONS: Thus, ARF and rhIGF-I treatment each affected certain serum IGFBPs and jointly affected some IGFBPs. ARF suppressed gene transcription for renal cortical and medullary IGF-IR and some IGFBPs. rhIGF-I independently affected some renal cortical or medullary IGFBP mRNAs. rhIGF-I increased hepatic IGFBP-2 mRNA and serum IGFBP-2. These effects of ARF or rhIGF-I may influence rhIGF-I actions in rats with ischemic ARF.

Acute Kidney Injury↗
PubMed1998

Insulin-like growth factor system and the kidney: physiology, pathophysiology, and therapeutic implications.

The insulin-like growth factor (IGF) system, consisting of IGF-I and IGF-II, their binding proteins, and their receptors, is expressed in a spatial organization in the nephron, but circulating IGFs also affect the kidney. Renal and systemic IGF-I and the binding proteins are regulated by growth hormone and nutritional status. In the kidney, IGF-I dilates the resistance-regulating microvasculature, increases glomerular filtration rate, and promotes tubular phosphate and possibly sodium absorption. IGF-I contributes to compensatory renal growth in a variety of experimental models and may modestly contribute to progressive glomerular sclerosis. In chronic renal failure and the nephrotic syndrome, there are several abnormalities in the IGF system. In chronic renal failure, IGF-I increases renal function and may improve nutritional status due to its anabolic effects. IGF-I accelerates the recovery of renal function in animal models of acute renal failure, but results from clinical trials were less salutary. Several questions regarding the role of the IGF system in normal and abnormal renal biology and potential therapeutic applications in kidney diseases remain unanswered.

Acute Kidney Injury↗
PubMed1998

Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis in native kidneys.

A circulating glomerular capillary albumin permeability factor (P(alb)) has been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), which recurs in transplanted kidneys. Plasmapheresis for recurrent FSGS may reduce proteinuria and stabilize renal function if instituted early. We performed six plasmapheresis treatments over 2 weeks in eight patients with a history of steroid-resistant idiopathic FSGS in native kidneys for an average of 12 +/- 2.3 months to determine whether treatment would decrease proteinuria or stabilize renal function. P(alb) was measured before and after plasmapheresis, and patients were followed-up for a mean of 29 +/- 4 months after the development of clinical symptoms. Proteinuria decreased in two of eight treated patients, although only transiently in one of the two. P(alb) improved in one of the two responding patients. Both patients with an improvement in proteinuria had stable renal function at last follow-up. In six of eight patients, there was no improvement in proteinuria despite an improvement in P(alb) (P < 0.0001) after plasmapheresis. At last follow-up, renal function was stable in two of the six nonresponding patients, and four of the six had significant progression of renal disease or were receiving dialysis treatments. These studies suggest that plasmapheresis may diminish proteinuria and stabilize renal function in a small minority of patients with steroid-resistant idiopathic FSGS. However, the lack of a relationship between the removal of the circulating permeability factor and the development of remission in these patients suggests that local factors associated with advanced renal injury or systemic factors unrelated to glomerular permeability play a significant role in determining proteinuria at this late stage of the disease.

Adolescent↗
PubMed1998

Mechanisms of insulin-like growth factor-I-induced accelerated recovery in experimental ischemic acute renal failure.

Exogenous administration of recombinant human insulin-like growth factor I (rhIGF-I) to normal rats or humans increases renal blood flow and glomerular filtration rate (GFR). In rats with ischemic acute renal failure (iARF) the peptide accelerates the recovery of renal function and tubular integrity. These latter effects may be caused by renal hemodynamic actions of IGF-I or may result from direct actions of IGF-I on injured tubular cells. To examine this hypothesis, in vivo studies were performed in rats with iARF and in vitro experiments were conducted using a model of anoxia/reoxygenation injury in primary cultures of rat proximal tubular cells. In rats with iARF, IGF-I ameliorates the rise in serum creatinine, improves GFR, increases the rate of bromodeoxyuridine (BrdU) incorporation and the mitosis score, and reduces the number of apoptotic bodies. In acutely injured proximal tubular cells, IGF-I receptor mRNA levels decrease, but the remaining receptors are functional as indicated by ligand-induced phosphorylation of the IGF-I receptor beta-subunit. In anoxia/reoxygenation-injured cells, exogenous rhIGF-I improves ATP repletion, increases 3H-thymidine and BrdU incorporation and reduces the incidence of apoptosis as determined by the TUNEL method. We conclude that rhIGF-I accelerates the recovery of renal function in rats with iARF probably through hemodynamic effects, but in addition through direct metabolic, mitogenic and antiapoptotic actions on injured tubules.

Acute Kidney Injury↗
PubMed1998

Growth factors and acute renal failure.

During acute renal injury, there are alterations in the expression of several growth factors and their receptors in the kidney. The increased expression of several growth factors and/or their receptors at sites of nephron injury suggests important contributions to repair. Exogenous administration of some growth factors, such as IGF-I, EGF and HGF, accelerates recovery of renal function in experimental acute renal failure (ARF). In ARF growth factors act through several mechanisms, which may include altered cell cycle regulation and mitogenesis, differentiation of recovered cells, regulation of apoptosis, improved renal hemodynamics, and others. There is evidence for interactions of growth factors with other growth factors as well as with other genes resulting in complex orchestration of biologic events contributing to recovery from ARF.

Acute Kidney Injury↗
PubMed1997

Role of growth factors in acute renal failure.

EGF, IGF-I, and HGF are involved in the endogenous tissue repair after acute renal injury. All three growth factors accelerate the recovery of renal function and the anatomical restoration of tubular integrity when given exogenously to laboratory animals with experimental ARF. However, clinical study of the therapeutic efficacy of recombinant peptide growth factors in ARF is limited to rhIGF-I. Both clinical trials of rhIGF-I in patients with ARF have been indeterminant or negative. Thus, the therapeutic use of peptide growth factors may not be the magic bullet for the cure of a disease that contributes significantly to morbidity and mortality in severely ill patients. However, there is ample experimental basis for further clinical study of recombinant human peptide growth factors in ARF.

Acute Kidney Injury↗
PubMed1996

Bioactivity of glomerular ultrafiltrate during heavy proteinuria may contribute to renal tubulo-interstitial lesions: evidence for a role for insulin-like growth factor I.

Clinical and experimental data have indicated that heavy proteinuria in renal glomerular diseases is associated with the formation of tubulo-interstitial fibrosis and contributes to the progression of renal failure. Albumin in glomerular ultrafiltrate does not appear to cause this sequelae, rather than compounds that are associated with ultrafiltered plasma proteins. One such protein-bound factor could be insulin-like growth factor I (IGF-I). The present studies show that in nephrotic rats, IGF-I is ultrafiltered in conjunction with IGF-binding protein-2 and is present in proximal tubular fluid at 1.35 nM. Proximal tubular fluid from nephrotic rats autophosphorylates IGF-I receptors in cultured proximal tubular cells. Nephrotic, but not control, rat proximal tubular fluid increases the [3H]thymidine incorporation in cultured tubular cells, and neutralizing IGF-I-receptor antibodies partially inhibit this activity. Incubation of cultured proximal tubular cells with an extract that was prepared from nephrotic rat urine increases the secretion of collagen types I and IV. Secretion of the two collagens is in part ameliorated by neutralizing IGF-I-receptor antibody. In concert, these findings suggest that the IGF-I present in nephrotic rat tubular fluid is bioactive and may contribute to the development of tubulo-interstitial fibrosis in chronic nephrotic glomerular diseases.

Animals↗
PubMed1996

Impaired actions of insulin-like growth factor 1 on protein Synthesis and degradation in skeletal muscle of rats with chronic renal failure. Evidence for a postreceptor defect.

The actions of insulin-like growth factor 1 (IGF-1) on protein turnover and of the IGF-1 receptor (IGF-1R) were examined in skeletal muscle of rats with chronic renal failure (CRF) and sham operated (SO), pair-fed controls. Acidemia was prevented in CRF rats with NaHCO3. Serum IGF-1 and skeletal muscle IGF-1 and IGF-1 mRNA were reduced in CRF rats. Dose-response studies revealed impaired stimulation of protein synthesis and suppressed inhibition of protein degradation by IGF-1 in epitrochlearis muscle of CRF rats. Neither IGF-1 analogues with low affinity to IGF binding proteins nor proteinase inhibitors obliterated the IGF-1 resistance. In CRF rats, skeletal muscle IGF-1R mRNA was increased; displacement ligand binding studies and affinity labeling of the IGF-1R alpha subunit indicated increased total skeletal muscle IGF-1R number with normal affinity. However, both autophosphorylation of the IGF-1R beta subunit (i.e., IGF-1R tyrosine kinase) and the IGF-1R tyrosine kinase activity towards exogenous insulin receptor substrate-1, a natural substrate for IGF-1R tyrosine kinase, were reduced in CRF fats. These data indicate that in skeletal muscle of CRF rats there is resistance to the IGF-1 effects on protein synthesis and degradation and decreased IGF-1 and IGF-1 mRNA levels; IGF-1R mRNA and number are increased; but activity of IGF-1R tyrosine kinase is impaired. This postreceptor defect may be a cause of the skeletal muscle resistance to IGF-1 in CRF.

Animals↗