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)

Adequate glycemic control protects most patients with diabetes from nephropathy, but a substantial fraction of patients develop progressive disease despite lowering glycemia. We isolated mesangial cells (MC) from the glomeruli of mouse strains that model these two outcomes in patients with diabetes, namely those that have the propensity (ROP) or resistance (B6) to develop progressive diabetic nephropathy. We determined the nature and reversibility of changes in selected extracellular matrix-related molecules after chronic exposure to elevated glucose concentration. MC were exposed to 25 mmol/l glucose for 5 weeks followed by 6 mmol/l glucose and 19 mmol/l mannitol for an additional 5 weeks. Matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta(1) (TGF-beta(1)) levels increased in B6 MC exposed to 25 mmol/l glucose but returned to baseline levels when the glucose concentration was reduced to 6 mmol/l. MMP-2 and TGF-beta(1) were higher in ROP MC at baseline and increased in response to 25 mmol/l glucose, but remained elevated when glucose concentration was reduced. Type I collagen expression and accumulation increased in a reversible manner in B6 MC exposed to 25 mmol/l glucose. However, type I collagen expression was higher in ROP MC at baseline and remained unaffected by changes in glucose concentration. Thus, 25 mmol/l glucose induced reversible changes in MMP-2, TGF-beta(1), and type I collagen in MC of sclerosis-resistant mice but not in MC from sclerosis-prone mice. Therefore, progressive diabetic nephropathy may be secondary to stable alterations in the phenotype of MC as a result of the interplay between the genetic background and elevated glucose concentrations.
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PMID:Reversibility of glucose-induced changes in mesangial cell extracellular matrix depends on the genetic background. 1181 61

The genetic background plays an important role in the development of progressive glomerulosclerosis. However, no marker is available for the reliable prediction of genetic susceptibility to glomerulosclerosis. Because matrix metalloproteinase-9 (MMP-9) levels are decreased in models of glomerulosclerosis and MMP-9 promoter polymorphism has been observed among patients with diabetic nephropathy, MMP-9 could be one such marker. The object of this study was to determine whether MMP-9 promoter polymorphism was associated with altered MMP-9 expression in mesangial cells (MC) from two mouse strains, i.e., ROP (glomerulosclerosis prone) and B6SJL (glomerulosclerosis resistant). ROP MC expressed 12-fold less MMP-9 mRNA. The MMP-9 promoter in ROP MC contained fewer d(CA) repeats, which was associated with lower MMP-9 expression and activity. Phorbol-12-myristate-13-acetate (3 to 60 ng/ml) increased MMP-9 expression in both MC types (3- to 4.5-fold), but the level in ROP MC never reached that in B6SLJ MC. Although reciprocal transfection of ROP and B6SJL MMP-9 promoter constructs into B6SJL and ROP cells revealed that the promoters were functional in both cell types, the B6SJL promoter was less responsive to phorbol-12-myristate-13-acetate stimulation when transfected into ROP MC, suggesting a role for other factors. In conclusion, the MMP-9 promoter exhibits a decreased number of d(CA) repeats in the sclerosis-prone strain. Because fewer d(CA) repeats associated with decreased MMP-9 expression in MC, it might be a genetic marker for glomerulosclerosis.
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PMID:Association of a decreased number of d(CA) repeats in the matrix metalloproteinase-9 promoter with glomerulosclerosis susceptibility in mice. 1213 38

Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase. The family of NADPH oxidase (Nox) enzymes are likely to be important given that their primary function is to produce ROS. Seven isoforms of Nox have been identified named Nox1-5, Duox (dual oxidase) 1 and Duox2. Nox1, Nox2 and Nox4 have been most extensively studied and are implicated in the development of conditions such as hypertension, cardiovascular disease and diabetic nephropathy. In recent years, evidence has accumulated to suggest that Nox1, Nox2 and Nox4 participate in pathological angiogenesis; however, there is no clear consensus about which Nox isoform is primarily responsible. In terms of retinopathy, there is growing evidence that Nox contribute to vascular injury. The RAAS (renin-angiotensin-aldosterone system), and particularly AngII (angiotensin II), is a key stimulator of Nox. It is known that a local RAAS exists in the retina and that blockade of AngII and aldosterone attenuate pathological angiogenesis in the retina. Whether the RAAS influences the production of ROS derived from Nox in retinopathy is yet to be fully determined. These topics will be reviewed with a particular emphasis on ROP and DR.
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PMID:Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy. 2337 42