Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The non-obese diabetic mouse is a model of spontaneous insulin-dependent diabetes as a result of autoimmune destruction of pancreatic beta cells, similar to the disease seen in human Type I diabetes. This mouse strain develops glomerular lesions reminiscent of those seen in human disease. The study presented here investigated the changes in renal insulin-like growth factor (IGF) system in hyperglycemic non-obese diabetic mice. Female non-obese diabetic mice and their age- and sex-matched controls were euthanized 4 days, 2 wk, and 4 wk after the onset of glycosuria. Kidney weight increased in diabetic mice, beginning at 2 wk after the onset of glycosuria. This renal hypertrophy was associated with an increase in renal extractable IGF-I protein. However, a decrease in IGF-I mRNA was observed at the same time. Serum IGF-I levels remained stable after 2 wk of diabetes and decreased at 1 month. No change was detected in renal IGF-I receptor mRNA levels. Renal cortical IGF binding protein (IGFBP)-1 mRNA levels were increased. Ligand blot analysis revealed a significant increase in serum and renal 30-kd IGFBP and a decrease in serum and kidney IGFBP-3 and IGFBP-4 at 30 days of diabetes. Insulin therapy prevented the increases in kidney weight, renal IGF-I, and 30-kd IGFBP, but did not reverse the decreased serum IGF-I levels observed at 1 month of diabetes. In summary, renal hypertrophy in non-obese diabetic mice is associated with a persistent accumulation of renal IGF-I and, IGFBP-1. These changes were partially reversed with insulin therapy, which did not correct the hyperglycemia, suggesting an important role for insulin deficiency in mediating these changes in the IGF system. These findings suggest that the IGF system may play a potential role in the development of diabetic nephropathy.
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PMID:Renal hypertrophy in hyperglycemic non-obese diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I. 907 12

Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function. To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age- and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means+/-s.e.m. Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation analysis. Type 1 diabetics showed significantly lower IGF-I (119+/-8 ng/ml) and IGFBP-3 (2590+/-104 ng/ml) but higher IGFBP-1 levels (38+/-10 ng/ml) compared with Type 2 patients (170+/-13, 2910+/-118, 11+/-3 respectively; P<0.05) or healthy controls (169+/-5, 4620+/-192, 3.5+/-0.4 respectively; P<0.01). IGFBP-5 levels were markedly lower in both diabetic groups (Type 1, 228+/-9; Type 2, 242+/-11 ng/ml) than in controls (460+/-7 ng/ml,P<0. 01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlated positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (83+/-2 %, Z-score) and lumbar spine (93+/-2 %) than Type 2 diabetics (93+/-5 %, 101+/-5 % respectively), reaching significance in the female subgroups (P<0.05). In Type 1 patients, BMD of hip correlated negatively with IGFBP-1 (r=-0.34, P<0.05) and IGFBP-4 (r=-0.3, P<0.05) but positively with IGFBP-5 (r=0.37, P<0. 05), which was independent of age, diabetes duration, height, weight and body mass index, as assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant positive correlations were found between proinsulin and BMD of hip (r=0.63, P<0.005), IGF-I (r=0.59, P<0.01) as well as IGFBP-3 (r=0.49, P<0.05). Type 1 and Type 2 patients with macroalbuminuria showed a lower BMD of hip, lower IGFBP-5 but higher IGFBP-4 levels, suggesting that diabetic nephropathy may contribute to bone loss by a disturbed IGF system. In conclusion, the findings of this study support the hypothesis that the imbalance between individual IGF system components and the lack of endogenous proinsulin may contribute to the lower BMD in Type 1 diabetics.
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PMID:Serum levels of insulin-like growth factor system components and relationship to bone metabolism in Type 1 and Type 2 diabetes mellitus patients. 979 71

The renal insulin-like growth factor-I (IGF-I) system has been implicated in the pathogenesis of renal hypertrophy, altered hemodynamics, and extracellular matrix expansion associated with early diabetes. The relative abundance of IGF binding proteins (IGFBPs) in the renal microenvironment may modulate IGF-I actions. However, the precise IGFBPs expressed in the glomerular and tubulointerstitial compartments during diabetic renal growth have not been characterized. In the present study, in situ hybridization studies were performed to examine the expression of IGFBP-1 to -6 messenger RNAs (mRNAs) 3, 7, and 14 days after streptozotocin (STZ) injection in rats. In control, nondiabetic kidneys, all six IGFBP mRNAs were differentially expressed with a predominance of IGFBP-5. The onset of renal hypertrophy in STZ-induced diabetes was associated with a rapid and site-specific induction of IGFBP-1, -3, and -5 mRNAs. In contrast, basal expression of IGFBP-2, -4, and -6 mRNAs was not altered in diabetic rats. IGFBP-5 mRNA expression increased in diabetic glomeruli, cortical, and inner medullary peritubular interstitial cells at days 3, 7, and 14. Although normal glomeruli failed to express IGFBP-3, it was induced concomitantly with IGFBP-5 in diabetic glomeruli and cortical peritubular interstitial cells. IGFBP-1 mRNA levels also increased in cortical tubular cells at each time point tested. Peak induction of IGFBP-3 and -5 was observed at day 3, whereas IGFBP-1 was delayed until day 7. IGFBP-1, -3, and -5 mRNA levels declined by day 14, but remained persistently elevated above control. By immunoperoxidase staining, similar alterations in the pattern of IGFBP-3 and -5 protein expression were observed at each time point. The preferential and site-specific increase in IGFBP-1, -3, and -5 suggest that these IGFBPs may regulate the local autocrine and/or paracrine actions of IGF-I and contribute to the pathogenesis of the early manifestations of diabetic nephropathy.
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PMID:Preferential expression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabetic renal hypertrophy in rats. 985 16

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.
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PMID:Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy. 1044 29

Mesangial cells are critical for glomerular filtration. Mesangial cell dysfunction, the hallmark of diabetic nephropathy, results from disordered mesangial growth induced by cytokines, abnormal hemodynamic influence, and metabolic factors associated with chronic hyperglycemia. Insulin-like growth factors (IGFs) and their high affinity binding proteins (IGFBPs) exert major actions on mesangial cell survival, but their underlying mechanisms remain unclear. In light of emerging IGF-independent roles for IGFBP-3, we investigated IGFBP-3 actions during mesangial cell apoptosis induced by cytokine or high glucose concentration. Quantified by DNA fragmentation ELISA and Annexin V flow cytometry, apoptosis occurred in rat mesangial cells (RMC) exposed to 2 microg/mL IGFBP-3 for 24 h under high ambient or standard glucose. Anti-sense IGFBP-3 oligo at 10 microg/mL significantly inhibited apoptosis induced by 100 ng/mL TNF-alpha, serum-free conditions, or high (25 mM) glucose. Increased IGFBP-3 release associated with high ambient glucose or TNF-alpha was inhibited by pre-treatment with anti-sense oligo. Under serum-free conditions, recombinant human IGFBP-3 blocked Akt phosphorylation at threonine 308 (pThr308), whereas anti-sense oligo treatment was associated with enhanced pThr308 activity. In summary, these data support a novel mechanism for TNF-alpha-induced mesangial cell apoptosis mediated by IGFBP-3 and present regulation of pThr308 activity as a novel mechanism underlying IGFBP-3 action.
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PMID:Insulin-like growth factor binding protein-3 mediates cytokine-induced mesangial cell apoptosis. 1593 83

Mechanisms contributing to development of diabetic nephropathy (DN) remain unclear. High ambient glucose level transforms intracellular pathways, promoting stable phenotypic changes in the glomerulus such as mesangial cell hypertrophy, podocyte apoptosis, and matrix expansion. Insulin-like growth factors (IGFs) and the high affinity IGF binding proteins (IGFBPs) exert major effects on cell growth and metabolism. Compared with diabetic patients without microalbuminuria (MA), MA diabetic patients display perturbed GH-IGF-IGFBP homeostasis, including increased circulating IGF-I and IGFBP-3 protease activity, increased excretion of bioactive GH, IGF-I, and IGFBP-3, but decreased circulating IGFBP-3 levels. In diabetic animal models, expression of IGF-I and IGFBP-1 to -4 increases in key renal tissues and glomerular ulrafiltrate. Epithelial, mesangial, and endothelial cells derived from the kidney respond to IGF-I binding with increased protein synthesis, migration, and proliferation. This article reviews classic and emerging concepts for the roles of the GH-IGF-IGFBP axis in the etiopathophysiology, treatment, and prevention of diabetic renal disease. We report IGF-independent actions of IGFBP-3 in the podocyte for the first time.
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PMID:Novel roles of the IGF-IGFBP axis in etiopathophysiology of diabetic nephropathy. 1701 63

The growth hormone-insulin-like growth factor-insulin-like growth factor binding protein (GH-IGF-IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF-IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH-IGF-IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.
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PMID:The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities. 2688 6