Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prepubertal onset of diabetes mellitus (DM) in male rats delays diabetic renal hypertrophy and suppresses renal transforming growth factor-beta (TGF-beta) compared with onset in adults. Because there are sex differences in normal and pathological renal growth, we performed similar experiments in female rats and examined the effects of prior ovariectomy. As in male rats, adult onset of DM increased renal weight approximately 35%, total renal TGF-beta approximately 35%, and mRNA for TGF-beta inducible gene H3 (betaIG-H3) approximately 200%. TGF-beta levels did not increase with DM in prepubertal animals, but renal weight increased approximately 40%, similar to the enlargement seen in adults. In nondiabetic rats, ovariectomy suppressed renal TGF-beta levels by 25-50% in both age groups, but betaIG-H3 was stable in younger animals and increased by approximately 200% in older animals after ovariectomy. Ovariectomy increased kidney weight approximately 10% in both age groups. DM further increased kidney weight by an additional 40% after ovariectomy with an approximately 150% increase in betaIG-H3, even though TGF-beta levels were not significantly increased. Prepubertal (approximately 99% lower), diabetic (approximately 50% lower), and ovariectomized rats (approximately 90% lower) all tended toward lower estradiol levels than intact adults, although not all differences were statistically significant. Both prepubertal onset and ovariectomy suppress TGF-beta in the kidneys of female rats with DM compared with adult-onset animals, but these states have no effect on renal enlargement. Production of the extracellular matrix component betaIG-H3 is dissociated from TGF-beta under these conditions. These observations may help explain some of the sex differences demonstrated in progressive kidney diseases, including DM.
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PMID:Dissociation of renal TGF-beta and hypertrophy in female rats with diabetes mellitus. 1528 Jan 57

The protective factor of female gender appears to be lost in diabetes; the incidence of diabetes and its complications, including diabetic nephropathy, are equal in women and men. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and replacement with 17beta-estradiol (OVX+E2) on renal function and pathology in the nondiabetic (ND) and streptozotocin (STZ)-induced diabetic (D) rat kidneys for 12 wk. Diabetes was associated with an increase in urine albumin excretion (UAE; ND, 0.39 +/- 0.03; D, 5.9 +/- 0.8 mg/day; P < 0.001), decrease in creatinine clearance (CrCl; ND, 0.69 +/- 0.03; D, 0.43 +/- 0.09 mg x min(-1) x 100 g body wt(-1); P < 0.05), increase in the index of glomerulosclerosis [GSI; ND, 0.01 +/- 0.01; D, 0.15 +/- 0.04 arbitrary units (AU); P < 0.01], tubulointerstitial fibrosis (TIFI; ND, 0.04 +/- 0.04; D, 0.68 +/- 0.2 AU; P < 0.01), and transforming growth factor-beta (TGF-beta) protein expression (ND, 0.61 +/- 0.02; D, 1.25 +/- 0.07 AU; P < 0.01). In the D group, the severity of these changes was augmented with OVX (UAE, 8.1 +/- 0.6 mg/day; CrCl, 0.40 +/- 0.04 mg x min(-1) x 100 g body wt(-1); GSI, 0.29 +/- 0.04 AU; TIFI, 0.90 +/- 0.06 AU; TGF-beta, 1.26 +/- 0.10 AU), whereas E2 replacement attenuated these changes (UAE, 6.3 +/- 0.8 mg/day; CrCl, 0.66 +/- 0.03 mg x min(-1) x 100 g body wt(-1); GSI, 0.06 +/- 0.02 AU; TIFI, 0.36 +/- 0.08 AU; TGF-beta, 0.57 +/- 0.08 AU). We conclude that E2 deficiency increases the severity of renal disease in a diabetic animal model and that E2 replacement is renoprotective by attenuating the decline in renal function and pathology associated with diabetes.
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PMID:17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. 1545 92

Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-beta (TGF-beta) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the high-glucose-induced overexpression of TGF-beta, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-beta expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy.
Diabetes 2005 Jan
PMID:Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. 1561 35

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta), and TGF-beta type II receptor (TGF-betaRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-beta as well as protein levels of CTGF and TGF-betaRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-beta mRNA levels expressed relative to beta-actin mRNA levels and CTGF and TGF-betaRII protein levels were significantly increased in D and D+I rats compared with C rats (P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-betaRII, and collagen I, mesangial cells (MC) were treated with BK (10(-8) M) for 24 h and CTGF and TGF-betaRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-betaRII protein levels was observed in response to BK stimulation (P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10(-8) M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK (P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 microM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-betaRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10(-8) M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-betaRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-betaRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.
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PMID:Mechanisms through which bradykinin promotes glomerular injury in diabetes. 1569 59

We have previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the transforming growth factor-beta (TGF-beta)-induced expression of extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. To test in vivo the antifibrotic efficacy of Ac-SDKP, we examined whether long-term Ac-SDKP treatment can prevent renal insufficiency and glomerulosclerosis in diabetic db/db mice. Diabetic db/db mice or nondiabetic db/m mice were treated with Ac-SDKP for 8 weeks using osmotic minipumps. The treatment with Ac-SDKP increased plasma Ac-SDKP concentrations by approximately threefold in both groups but did not affect the blood glucose levels. Histologically, the increased glomerular surface area, mesangial matrix expansion, and overproduction of extracellular matrix proteins in db/db mice were significantly inhibited by Ac-SDKP. Furthermore, Ac-SDKP treatment normalized the increased plasma creatinine value in db/db mice, whereas the albuminuria in Ac-SDKP-treated db/db mice was somewhat decreased as compared with nontreated db/db mice, although the difference was not statistically significant. In addition, the nuclear translocation of Smad3 was inhibited by Ac-SDKP. These results demonstrate that long-term Ac-SDKP treatment ameliorates renal insufficiency and glomerulosclerosis in db/db mice via inhibition of TGF-beta/Smad pathway, suggesting that Ac-SDKP could be useful in the treatment of diabetic nephropathy.
Diabetes 2005 Mar
PMID:N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice. 1573 63

Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P < 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.
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PMID:Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. 1575 59

CD4+ CD25+ T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency and function of CD4+ CD25+ T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between increasing age and CD4+ CD25+ T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients, similar frequencies of CD4+ CD25+ and CD4+ CD25(+Bright) T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD4+ CD25+ or CD4+ CD25(+Bright) T-cell frequency. However, type 1 diabetic patients were markedly defective in their ability to suppress the proliferation of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced production of interleukin (IL)-2, gamma-interferon, and transforming growth factor-beta, whereas other cytokines including those of adaptive and innate immunity (IL-10, IL-1beta, IL-6, IL-8, IL-12p70, and tumor necrosis factor-alpha) were similar in control subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD4+ CD25+ T-cells and that function, rather than frequency, may represent the means by which these cells associate with type 1 diabetes in humans.
Diabetes 2005 May
PMID:Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. 1585 27

The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-beta (TGF-beta) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-beta and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-beta as determined immunohistochemically. The levels of TGF-beta and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-beta and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.
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PMID:Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression. 1585 46

Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
Diabetes 2005 Jun
PMID:From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. 1591 82

A key goal of cellular engineering is to manipulate progenitor cells to become beta-cells, allowing cell replacement therapy to cure diabetes mellitus. As a paradigm for cell engineering, we have studied the molecular mechanisms by which AR42J cells become beta-cells. Bone morphogenetic proteins (BMPs), implicated in a myriad of developmental pathways, have not been well studied in insulin-positive differentiation. We found that the canonical intracellular mediators of BMP signaling, Smad-1 and Smad-8, were significantly elevated in AR42J cells undergoing insulin-positive differentiation in response to exendin-4 treatment, suggesting a role for BMP signaling in beta-cell formation. Similarly, endogenous BMP-2 ligand and ALK-1 receptor (activin receptor-like kinase-1; known to activate Smads 1 and 8) mRNAs were specifically up-regulated in exendin-4-treated AR42J cells. Surprisingly, Smad-1 and Smad-8 levels were suppressed by the addition of BMP-soluble receptor inhibition of BMP ligand binding to its receptor. Here, insulin-positive differentiation was also ablated. BMP-2 ligand antisense also strongly inhibited Smad-1 and Smad-8 expression, again with the abolition of insulin-positive differentiation. These results demonstrate a previously unrecognized key role for BMP signaling in mediating insulin-positive differentiation through the intracellular Smad signaling pathway. In short, BMP signaling may represent a novel downstream target of exendin-4 (glucagon-like peptide 1) signaling and potentially serve as an upstream regulator of transforming growth factor-beta isoform signaling to differentiate the acinar-like AR42J cells into insulin-secreting cells.
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PMID:Cross-talk between bone morphogenetic protein and transforming growth factor-beta signaling is essential for exendin-4-induced insulin-positive differentiation of AR42J cells. 1602 May 42


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