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)

We investigated serum levels of type III procollagen aminopeptide (CIII), 7S type IV collagen (CIV), and tissue inhibitor of metalloproteinase (TIMP) in 33 patients with type II diabetes mellitus (DM) without uremia (serum creatinine less than 1.5 mg/dl). The patients were divided into three groups based on measurement of the urinary albumin excretion (UAE) index obtained during two morning outpatient clinic visits: non-proteinuric patients (n = 11), UAE index less than 2.26 mg/mmol Cr; patients with microalbuminuria (n = 15), UAE index of 2.26 - 22.6 mg/mmol Cr; and patients with proteinuria (n = 7), UAE index more than 22.6 mg/mmol Cr. Serum levels of CIV and TIMP in patients with microalbuminuria and proteinuria were significantly higher than non-proteinuric patients (ANOVA, p <0.05). Serum levels of CIII in patients with proteinuria were significantly higher than those in non-proteinuric patients (p < 0.05). There was a significant positive correlation between CIV and TIMP (r = 0.502, p < 0.003), but no correlation was observed between CIII and TIMP. These results demonstrated that serum CIII and CIV increases as diabetic nephropathy progresses in terms of increasing proteinuria in type II DM patients, suggesting feasibility and usefulness of measuring serum CIV and CIII in assessing diabetic nephropathy. The increase in TIMP may be, at least in part, a possible cause for the increase in serum CIV in type II DM patients.
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PMID:Serum type III, IV collagens and TIMP in patients with type II diabetes mellitus. 861 90

Mesangium enlargement and glomerular basement membrane thickening are cardinal features of diabetic nephropathy. The reasons for these changes are uncertain but decreased degradation of extracellular matrix may play a role. Mesangium degradation can be modulated by factors intrinsic to the kidney or by factors in the circulation. In this study the capacity of leucocyte proteolytic enzymes to degrade mesangium matrix materials was investigated. Leucocytes were obtained from 57 patients with NIDDM (age 58.3 +/- 8.8 years, duration 9.4 +/- 7.3 years, body mass index (BMI) 30 +/- 6 kg m-2, HbA1c 7.7 +/- 2.0%) and 21 control subjects (age 55.1 +/- 14.6 years, BMI 25 +/- 4 kg m-2). Leucocyte lysates from control and NIDDM subjects with normal AER degraded matrix to the same extent (40.6 +/- 8.2% vs 42.9 +/- 13.5%) while lysates from patients with microalbuminuria and proteinuria were less able to degrade matrix (33.0 +/- 14.2% and 26.1 +/- 12.7%, respectively). There was a significant inverse correlation between matrix degradation and AER (r = -0.49) and multiple regression analysis showed that AER was the most important factor determining degradation rate (R2 = 0.24). Degree of metabolic control, age, and blood pressure were not significant factors. The major enzyme(s) responsible for the matrix degradation was identified as metalloproteinase(s). We conclude that leucocytes from diabetic patients with abnormal albumin excretion have a decreased proteolytic capacity to degrade extracellular matrix. This may play a role in the glomerular basement membrane thickening and mesangium expansion which occurs in diabetic nephropathy.
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PMID:Reduction of leucocyte proteolytic enzyme activity in diabetic patients with microalbuminuria and proteinuria: its possible role in diabetic nephropathy. 864 Nov 19

Diabetic nephropathy is a common cause of end-stage renal disease. The administration of an oral adsorbent, AST-120, prevents the progression of chronic renal failure in uremic rats and undialyzed uremic patients. This study was designed to determine if AST-120 slows the progression of diabetic nephropathy using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetic mellitus. At 21 weeks of age the OLETF rats were divided into 2 groups: AST-120-administered OLETF rats (n = 7), and control OLETF rats (n = 7). LETO rats, which are genetically similar to the OLETF rats but not diabetic, were also included. After the oral administration of AST-120 for 65 weeks, renal function and pathological changes were investigated in the 3 groups. The administration of AST-120 to the OLETF rats attenuated the progression of glomerular sclerosis, interstitial fibrosis, tubular injury as well as renal dysfunction, and reduced the serum and urinary levels of indoxyl sulfate. Furthermore, AST-120 administration reduced the interstitial expression of transforming growth factor (TGF)-beta(1) and tissue inhibitor of metalloproteinase (TIMP)-1, as well as interstitial infiltration of macrophages. The TGF-beta(1)-stained interstitial area showed positive correlations with the interstitial fibrosis area, the number of TIMP-1-positive cells, and the number of macrophages, and showed a negative correlation with creatinine clearance. In conclusion, AST-120 reduced the interstitial expression of TGF-beta(1) and TIMP-1, and the interstitial infiltration of macrophages, and ameliorates the progression of diabetic nephropathy in OLETF rats.
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PMID:Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-beta(1) expression in spontaneously diabetic (OLETF) rats. 1087 8

In the development of diabetic nephropathy, angiotensin (Ang) II is thought to exert numerous actions on the glomerulus, and especially on the mesangium. However, the role(s) played by Ang II in the glucose metabolism per se in mesangial cells remains unclear. Ang II, at least via its type 1 receptor (AT1-R)-mediated effect, phosphorylates extracellular signal regulated kinase (ERK) by transactivation of epidermal growth factor receptors (EGF-Rs) via the Ca2+ or protein kinase C (PKC) pathways. Our objective in the present study was to assess the effect of Ang II on glucose transporter 1 (GLUT1) gene expression and to clarify the involvement of EGF-R in Ang II-mediated GLUT1 mRNA expression in glomerular mesangial cells. The results showed that Ang II upregulated GLUT1 mRNA accumulation in a time- and dose-dependent manner (peaking at 12 h; approximately 3.8-fold vs. control), and this upregulation was completely inhibited by the PKC inhibitor calphostin-C. The Ang Il-induced GLUT1 expression was significantly inhibited by the EGF-R inhibitor AG1478 (approximately 80% inhibition), by inactivation of ERK by PD98059, and by pretreatment with heparin and the metalloproteinase (MMP) inhibitor batimastat. On the other hand, phorbol ester markedly upregulated GLUT1 mRNA (approximately 8.6-fold). Batimostat and AG1478 significantly reduced the phorbol ester-induced GLUT1 mRNA expression (approximately 72 and approximately 69% inhibition, respectively). In conclusion, PKC-mediated heparin-binding (HB)-EGF/EGF transactivation followed by ERK activation plays a predominant role in the induction of GLUT1 expression by Ang II.
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PMID:Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: involvement of HB-EGF and EGF receptor transactivation. 1266 15

The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia-induced alteration of the pattern of podocyte-integrin expression, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti-VEGF antibodies attenuates glomerular basement membrane thickening, platelet-derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation end-products but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified.
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PMID:Microvascular basement membranes in diabetes mellitus. 1284 21

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy.
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PMID:Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. 1504 30

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-beta (TGF-beta)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-beta1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-beta1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti-TGF-beta and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-beta, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection.
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PMID:Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. 1673 30

Meprin metalloproteinases have been implicated in the susceptibility to and progression of diabetic nephropathy and inflammatory bowel diseases. Our studies with experimental models of these diseases in mice are congruent with the conclusion that meprins modulate the inflammatory responses and tissue damage. To determine whether the mouse and human enzymes differ, recombinant forms of meprin A from the two species were compared with respect to structure, substrates and inhibitors. Human homo-oligomeric meprin A formed oligomers ranging from 950,000 to 1,500,000 Da vs. 900,000 Da for mouse meprin A. Human and mouse meprin A exhibited similar activity against azocasein, fibronectin, collagen IV, and peptides such as parathyroid hormone, ghrelin, and gastrin-releasing peptide. The human enzyme had lower activity against gelatin, bradykinin, alpha-melanocyte-stimulating hormone and neurotensin, and higher activity against secretin and orcokinin. Human meprin A showed a preference for acidic residues in the P1' position of the substrate, unlike mouse meprin A. Several metalloproteinase inhibitors had IC(50) values in the nanomolar range, but potency ranged from similar values to a difference of several orders of magnitude for meprins from the two species. This work provides valuable data to improve predictability for human systems based on meprin functions in mouse models.
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PMID:Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities. 1797 9

Pathological remodeling characterized by extracellular matrix (ECM) accumulation contributes to diabetic nephropathy (DN). This study evaluated the effects of Ginkgo biloba extract (GbE) on the metabolism of the ECM in rat mesangial cells cultured in hyperglycemic conditions. The cultured mesangial cells in high glucose conditions were allotted into six groups: normal control group, high glucose group, low concentration of GbE group, moderate concentration of GbE group, high concentration of GbE group, and captopril group. In the presence of high glucose, the levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and extracellular matrix metalloproteinase inducer (EMMPRIN) were decreased significantly, and the levels of tissue inhibitor of metalloproteinase-2 (TIMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) were increased significantly. These changes were reversed by GbE. GbE lowered the levels of transforming growth factor-beta(1) (TGF-beta(1)), insulin-like growth factor-1 (IGF-1) and connective tissue growth factor (CTGF) of the high glucose group. Furthermore, GbE also decreased the expressions of collagen IV and laminin of the high glucose group. In summary, the results suggest that GbE postpones the extracellular matrix accumulation by inhibiting the synthesis of ECM and promoting the degradation of ECM, and therefore, is a potential drug for the prevention and treatment of DN.
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PMID:Ginkgo biloba extract prevents glucose-induced accumulation of ECM in rat mesangial cells. 1900 45

The balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) determines the integrity of the extracellular matrix. TIMP3 is the most highly expressed tissue inhibitor of metalloproteinase (TIMP) in the kidney, but its function in renal disease is incompletely understood. In this study, TIMP3-/- mice demonstrated an age-dependent chronic tubulointerstitial fibrosis. After unilateral ureteral obstruction (UUO), young TIMP3-/- mice exhibited increased renal injury (tubular atrophy, cortical and medullary thinning, and vascular damage) compared with wild-type mice. In addition, TIMP3-/- mice had greater interstitial fibrosis; increased synthesis and deposition of type I collagen; increased activation of fibroblasts; enhanced apoptosis; and greater activation of MMP2, but not MMP9, after UUO. TIMP3 deficiency also led to accelerated processing of TNFalpha, demonstrated by significantly higher TACE activity and greater soluble TNFalpha levels by 3 d after UUO. The additional deletion of TNFalpha markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3-/-/TNFalpha-/- mice further abrogated postobstructive injury and prevented tubulointerestitial fibrosis. In humans, TIMP3 expression increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy. Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease.
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PMID:Loss of TIMP3 enhances interstitial nephritis and fibrosis. 1940 80


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