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 effect of the non-ionic contrast medium iohexol (Omnipaque) on renal function was investigated in diabetic patients with signs of peripheral ischaemia. Forty-six patients, 70 +/- 11 years (mean +/- SD) old, age at diabetes diagnosis 53 +/- 17 years, and with varying degrees of diabetic nephropathy were studied before 1, 2, and 30 days after aortobifemoral arteriography. Serum creatinine, creatinine clearance, urinary excretion of immunoglobulin G, albumin collagen IV (NC1), kappa and lambda chains, alpha-1 microglobulin and Tamm-Horsfall protein were evaluated. Within 1 month before and 30 days after arteriography, the glomerular filtration rate was measured by clearance of iohexol. The acute effect of the radiocontrast medium was an increase in the serum creatinine level in 41 (89%) patients, with a more than 25% increase in 12 (26%) patients. The excretion rates of immunoglobulin G and albumin decreased, whereas the proximal and distal tubular function and the excretion of collagen IV did not change. The increment in serum creatinine was associated with the preangiographic renal function (p < 0.05), a history of heart failure (p < 0.01), but not with age, duration and type of diabetes, gender, systolic or diastolic blood pressure, glycated haemoglobin (HbAlc) or blood glucose levels. The increase of serum creatinine was associated with a pre-existing proximal tubular dysfunction and a worsening of distal tubular function. No changes in the parameters measured persisted 30 days after angiography. In summary, a transient increment in serum creatinine level after arteriography occurred in 89% of diabetic patients. It was associated with the preangiographic renal function, a history of heart failure and signs of preexisting proximal tubular dysfunction and worsening of distal tubular function. However, these changes were reversible.
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PMID:The effect of the non-ionic contrast medium iohexol on glomerular and tubular function in diabetic patients. 873 33

An accurate assessment of which patient with glomerular disease will progress to end-stage renal failure would be an important addition to establishing prognosis and evaluating therapeutic strategies. We previously found the development of glomerular scarring in animal models was preceded by an increase in glomerular type IV collagen mRNAs and that the level of scarring predicted the rate of progression. The purpose of this study was to determine whether these findings apply to human glomerular diseases using microdissected glomeruli and assessment of mRNA by competitive PCR. After showing that the levels of type IV collagen mRNAs were elevated in sclerotic glomeruli isolated from nephrectomies, we undertook this preliminary cross-sectional study of type IV collagen subchain mRNAs in renal biopsies in two of the leading causes of glomerulosclerosis, diabetic nephropathy, and membranous glomerulopathy. We found that glomerular type IV collagen mRNA levels were altered in disease-specific ways. The relative levels of the individual alpha-chains of type IV collagen depended on the anatomic site of the glomerular lesions. The alpha 2 type IV/alpha 3 type IV collagen mRNA ratio was high in diabetes mellitus, but not in membranous glomerulopathy. These data, coupled with those obtained from experimental animals, suggest that a dysregulation of basement collagen synthesis underlies progressive glomerular scarring. If these conclusions are verified in prospective studies it will be feasible to assess the risk of developing progressive glomerulosclerosis in the individual patient and to quantitatively assess therapeutic responses in a timely manner.
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PMID:Molecular analysis of glomerular diseases in renal biopsies: initial results of a collaborative international study. The International Study Group for Molecular Study of Kidney Biopsies. 877 54

Diabetic nephropathy is associated with thickening of the glomerular basement membrane and, in particular, with mesangial matrix expansion. Previous studies have indicated that administration of chemically modified, low-anticoagulant heparins prevents some of the morphologic and physiologic alterations occurring in experimental diabetic nephropathy. The effect of prolonged heparin treatment on the glomerular expression and deposition of alpha 1 (IV) collagen, which is a major component of the mesangial matrix, has not been reported previously. Four groups of rats were studied for 12 months: two control groups and two groups of streptozotocin-diabetic rats. One group in each branch received modified heparin continuously from the induction of diabetes. After 12 months synthesis and deposition of alpha 1 (IV) collagglomerula and adjacent tubuli were determined by nonradioactive in situ hybridization and immunohistochemistry. Mesangial cells were localized by Thy 1.1 staining. Long-term diabetes caused a significant increase in alpha 1 (IV) collagen deposition in the mesangial matrix and a more than 2-fold enhancement of glomerular cell alpha 1 (IV) collagen transcript levels, mainly in mesangial cells. The alpha 1 (IV) collagen mRNA levels of proximal tubular cells and visceral epithelial cells were similarly increased. Chronic treatment of diabetic rats with modified heparin completely prevented the increased alpha 1 (IV) collagen deposition and expression. The increased glomerular deposition of alpha 1 (IV) collagen observed in long-term streptozotocin diabetic rats appears to depend on an increased alpha 1 (IV) collagen synthesis. Because chronic application of low-anticoagulant heparin completely prevents the increased alpha 1 (IV) collagen synthesis by mesangial cells, this result suggests a new therapeutic option for the prevention of diabetic nephropathy in humans.
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PMID:Increased glomerular alpha 1 (IV) collagen expression and deposition in long-term diabetic rats is prevented by chronic glycosaminoglycan treatment. 878 Jan 66

Accelerated nonenzymatic glycation in diabetes, resulting in Amadori-modified proteins and the later-developing advanced glycation end-products, has been mechanistically linked to the pathogenesis of diabetic nephropathy. Recent focus on putative AGE-induced pathophysiology has shifted attention from the possible role of Amadori-modified proteins in the development of diabetic complications. Ample experimental evidence has demonstrated that Amadori-modified serum proteins adversely affect renal glomerular capillary function, structure, and metabolism. Previous studies from the laboratories of this study's authors have shown that human serum containing diabetic concentrations of albumin modified by Amadori-glucose adducts inhibits the replication of murine mesangial cells in culture and stimulates the production and gene expression of type IV collagen. Monoclonal antibodies (A717) specific for Amadori-glycated albumin prevent these abnormalities. In other studies, it has also been shown that in vivo administration of A717 (Fab fragments) retards the progression of diabetic nephropathy in diabetic db/db mice. Neutralizing the effects of the elevated circulating glycated albumin concentration is associated with reduction in proteinuria and mesangial matrix expansion, and prevention of the overexpression of mRNA encoding type IV collagen and fibronectin in the renal cortex. The renoprotective effects of A717 are independent of any change in blood glucose concentrations. These studies implicate Amadori-modified glycated albumin in the pathogenesis of diabetic nephropathy. It is proposed in this study that abrogating the biologic effects of increased glycated albumin in diabetes has novel therapeutic potential in the management of diabetic renal complications.
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PMID:Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. 878 86

We examined glomerular basement membrane anionic site distribution identified by cationic gold in seven patients with insulin-dependent and four patients with non-insulin-dependent diabetes mellitus, presenting a spectrum of clinical and glomerular changes. Anionic sites were investigated by pretreatment of tissue with glycosaminoglycan-degrading enzymes prior to cationic gold staining. The distribution of chondroitin sulphate proteoglycans--a previously unrecognized glomerular basement membrane component--and type IV collagen was examined by immunoelectron microscopy to identify structural changes in the basement membrane. Findings were compared with those of non-diabetic patients showing minor proteinuria and morphologically normal glomerular basement membranes. Two patients, originally diagnosed as having diabetic nephropathy were also examined at 19 weeks and 5 years after renal transplantation. Characteristic redistribution of type IV collagen and chondroitin sulphate proteoglycans was noted in thickened glomerular basement membrane segments (> 400 nm) of diabetic patients and those with renal transplants. Extension of anionic sites deep into the glomerular basement membrane at pH 2.5, together with loss of interna sites at pH 5.8 is unique to diabetic nephropathy. Reduced charge density was apparent in some patients due to thickening of the glomerular basement membrane, although the number of anionic sites per unit length of membrane was actually increased. Thus, charge aberration in diabetic nephropathy is due to displacement rather than loss of anionic sites. Removal of more than 90% of these sites by heparitinase, confirms their association with heparan sulphate proteoglycans. Similar derangement of anionic sites in all patients with diabetic nephropathy irrespective of the degree of proteinuria, suggests that a heparan sulphate proteoglycan-related charge barrier plays a minor role in controlling permeability of the diabetic glomerular basement membrane.
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PMID:Alterations of glomerular basement membrane charge and structure in diabetic nephropathy. 878 20

To evaluate the significance of collagen levels, nonenzymatic glycation, and effective renal plasma flow in diabetes, we studied 52 Streptozocin induced-diabetic rats. After 10 weeks of diabetes, rats were injected i.v. 0.5 microCi/g 99mTechnetium Mercaptoacetyl triglycine and effective renal plasma flow was calculated from the renograms obtained. The collagen content and hydroxymethyl furfural levels of kidney and tail tissue as well as renal plasma flow increased significantly in diabetic rats (p < 0.05). The increase in renal plasma flow indicates that hyperperfusion may play a role in diabetic nephropathy mechanism. The correlation between renal plasma flow and glycation was not as high as the correlations between blood glucose concentrations and hydroxymethyl furfural and collagen levels, suggesting that factors other than glycation are important in increasing the renal plasma flow.
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PMID:The effects of streptozocin-induced diabetes on renal plasma flow. 878 9

We investigated the urinary secretion of type IV collagen in 115 subjects with non-insulin-dependent diabetes mellitus (NIDDM) without macroproteinuria, 34 normal healthy subjects and 19 subjects with chronic glomerulonephritis (CGN). We examined the relation between the urinary level of type IV collagen and various clinical parameters. The urinary level of type IV collagen was significantly elevated in NIDDM subjects compared with normal subjects (4.88 +/- 3.12 vs. 1.7 +/- 1.25 micrograms/gCr, P < 0.001). The urinary level of type IV collagen was increased even in NIDDM subjects with normoalbuminuria. The ratio of urinary type IV collagen was significantly lower in subjects with chronic glomerulonephritis (CGN) than those in NIDDM subjects (P < 0.001), although there was no significant difference in the urinary level of type IV collagen between NIDDM and CGN subjects. The ratio of urinary type IV collagen to albumin was under 10.0 x 10(-6) in all subjects with CGN. Our results suggest that measurement of the urinary level of type IV collagen is useful for detection of early diabetic nephropathy and for the differential diagnosis of diabetic nephropathy and chronic glomerulonephritis.
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PMID:Urinary type IV collagen as a marker for early diabetic nephropathy. 879 8

Overproduction of extracellular matrix (ECM) is considered to be primarily responsible for both glomerular and tubulointerstitial (TI) changes in diabetic nephropathy (DN). To clarify the possible role of the collagens in TI damage in DN, type III interstitial collagen and type IV basement membrane collagen were studied in 10 cases of DN and 10 control cases by immunohistochemistry and in situ hybridization techniques. In control cases, no immunostaining for type III collagen was found in the renal tubules, while strongly positive in the adjacent interstitium. On the other hand, type IV collagen was found weakly in the tubular basement membrane (TBM) in control cases. In DN, increased immunostaining for both type III and type IV collagens were found in the damaged tubulointenstitium (TI). To determine the sources of these collagens in TI damage, non-radioactive in situ hybridization was performed utilizing thymine-thymine (T-T) dimerized synthetic oligonucleotides complementary to either human pro alpha 1 (III) chain or pro alpha 1 (IV) chain mRNA as probe. In normal tubules, tubular epithelial cells were not uniformly but persistently positive for pro alpha 1 (IV) mRNA. Meanwhile, no specifically detectable positive hybridization signals for pro alpha 1 (III) mRNA was found in the normal tubular epithelial cells. Accelerated synthesis of both type III and type IV collagens by tubular epithelial cells was noted in TI damage in DN. From the results we concluded that excessive synthesis of both type III and type IV collagens by tubular epithelial cells might significantly contribute to the TI damage found in DN.
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PMID:Synthesis of type III collagen and type IV collagen by tubular epithelial cells in diabetic nephropathy. 882 11

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabry's disease, insulin in diabetic nephropathy, and the "minor" collagen IV chains in Alport's syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.
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PMID:Molecular therapy for renal diseases. 884 Sep 36

We determined serum levels of type IV collagen 7S (IV 7S) in 73 (23 with normoalbuminuria, 21 with microalbuminuria, 17 with macroalbuminuria, and 12 primarily affected by nondiabetic renal disease (NDRD)) and 24 (10 with only macroangiopathy and 14 with retinopathy and macroangiopathy) diabetic patients to see whether IV 7S can be a useful index for differentiating early or overt diabetic nephropathy from NDRD in micro- or macroalbuminuric diabetics. IV 7S was significantly elevated in diabetic patients with micro-or macroalbuminuria compared to those with normoalbuminuria and healthy controls (p < 0.001). On the contrary, all 12 diabetic patients with micro- or macroalbuminuria due to NDRD showed normal or low IV 7S level. IV 7S was significantly higher in diabetic patients with both retinopathy and macroangiopathy than in those with only macroangiopathy (p < 0.001). We conclude that IV 7S levels may be a useful index to differentiate diabetic early or overt nephropathy from NDRD, especially nephrosclerosis, in micro- or macroalbuminuric diabetics.
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PMID:Difference of serum levels of type IV collagen 7S between early or overt nephropathy and nondiabetic renal disease in diabetic patients with micro- or macroalbuminuria. 885 58


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