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)

The present study was undertaken to investigate whether matrix metalloproteinase (MMP) functions to prevent the occurrence of destructive fibrosis in progressive renal disease. As a sustained release carrier of plasmid DNA, biodegradable hydrogels and microspheres were formulated from cationized gelatin prepared through aminization. Plasmid DNA was released from the cationized gelatin hydrogels as a result of hydrogel degradation. A plasmid DNA including a cytomegalovirus promoter and human recombinant MMP-1 gene (pCMV-MMP) was constructed. Gelatin microspheres incorporating pCMV-MMP as well as phosphate-buffered saline (PBS) with or without pCMV-MMP were injected into the renal subcapsule of C57BL/6 mice, which were intraperitoneally injected with streptozotocin (STZ) to induce diabetes 7 days after operation. The mice were killed 4 weeks after STZ injection to sample their blood and kidneys for biochemical and histological examinations. An immunofluorescence study confirmed that MMP protein was expressed around the renal tissue injected with gelatin microspheres incorporating pCMV-MMP. When applied with cationized gelatin microspheres incorporating pCMV-MMP, the mice showed a level of blood urea nitrogen significantly lower than that of other groups. A reduced content of collagen in the kidneys of mice administered gelatin microspheres incorporating pCMV-MMP was histologically observed. Further, the hydroxyproline assay revealed a significantly decreased content of hydroxyproline in kidney. We conclude that sustained release of MMP-1 gene is a promising prophylactic trial for kidney fibrolysis and dysfunction in the STZ-induced diabetic mouse model.
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PMID:Local delivery of matrix metalloproteinase gene prevents the onset of renal sclerosis in streptozotocin-induced diabetic mice. 1467 37

Mesangial cells (MG) are an important source of renal PGE2 and PGI2. The purpose of this study was to examine the effects of cicaprost (CCP; PGI2 analog) on MG function and the expression of IP receptors in streptozotocin (STZ)-diabetic rats and glucose-treated MG cells. CCP increased cellular cAMP in immortalized rat MG cells. Both glucose and anisomycin attenuated CCP-cAMP, but not PMA, angiotensin II, or transforming growth factor-beta. Also, IP receptor protein was reduced in response to glucose. While CCP decreased the levels of the cell cycle inhibitor p27, it did not alter thymidine or leucine incorporation. However, CCP reduced fibronectin levels by 40% and increased matrix metalloproteinase-2 levels threefold, a key enzyme in matrix degradation. Finally, IP receptors were significantly reduced in the outer medulla of 4- and 12-wk STZ-diabetic rats and in the cortex, outer, and inner medullary regions in 6-mo uninephrectomized STZ-diabetic rats. The changes in the CCP/IP system observed in this study suggest that IP may serve as an alternate therapeutic target in diabetes.
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PMID:Reduced IP receptors in STZ-induced diabetic rat kidneys and high-glucose-treated mesangial cells. 1516 1

Diabetes increases susceptibility to chronic skin ulceration. The etiology of chronic wound formation in diabetic individuals is multifactoral but may be accelerated by changes in the structure and function of the skin secondary to impaired fibroblast proliferation, decreased collagen synthesis, and increased matrix metalloproteinase (MMP) expression. This study explored the effects of all-trans-retinoic acid (RA) on cellular and biochemical features of diabetic human skin in organ culture. Two-mm skin biopsies from hip or ankle were obtained from diabetic subjects and incubated for 9 days in the absence or presence of 2 micro mol/L RA. Hip skin from non-diabetic individuals served as control. Following organ culture incubation, untreated and RA-treated tissue was examined histologically after staining with hematoxylin and eosin. In parallel, organ culture-conditioned medium collected on days 5 and 7 was assayed for levels of active and total MMP-1 (interstitial collagenase) and MMP-9 (gelatinase B). The same organ culture fluids were assayed for the presence of soluble collagen. In comparison with skin from non-diabetic individuals, diabetic skin demonstrated no major differences in overall epidermal thickness or collagen production (both were increased in RA-treated tissue as compared to non-RA-treated tissue). In contrast, levels of MMP-9 (active forms) were elevated in organ culture fluid from diabetic skin as compared to non-diabetic control skin. In the presence of RA, active forms of both MMP-1 and MMP-9 were reduced. Together, these data suggest that RA has the capacity to improve structure and function of diabetic skin, and that a major effect is on reduction of collagen-degrading MMPs.
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PMID:All-trans-retinoic acid suppresses matrix metalloproteinase activity and increases collagen synthesis in diabetic human skin in organ culture. 1521 72

Long-standing diabetes can result in the development of cardiomyopathy, which can be accompanied by myocardial fibrosis. Although exposure of cultured kidney and skin fibroblasts to high glucose (HG) concentration is known to increase collagen synthesis, little is known about cardiac fibroblasts (CFs). Therefore, we determined the influence of HG conditions on CF functions and the effects of losartan and vitamin E in these responses. We cultured rat CFs in either normal glucose (NG; 5.5 mM) or HG (25 mM) media and assessed changes in protein and collagen synthesis, matrix metalloproteinase (MMP) activity, and levels of mRNA for ANG II type 1 (AT(1)) receptors. Results indicate that HG-level CFs synthesized more protein and collagen, and these effects were not due to changes in osmotic pressure. The addition of ANG II stimulated protein and collagen synthesis in NG-concentration but not HG-concentration CFs. Interestingly, losartan pretreatment blocked the HG- or ANG II-induced increases in both protein and collagen synthesis. HG or ANG II decreased total MMP activity. Decreases in MMP activity were blocked by losartan. AT(1) mRNA levels were upregulated with HG concentration. Vitamin E pretreatment blocked the effects of HG on total protein synthesis and stimulated MMP activity. Results suggest that HG levels may promote fibrosis by increasing CF protein and collagen synthesis and decreasing MMP activity. HG levels may cause these effects via the upregulation of AT(1) receptors, which can be blocked by losartan. However, vitamin E can alter HG concentration-induced changes in CF functions independently of AT(1) mRNA levels.
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PMID:Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E. 1534 78

High glucose concentration inhibits matrix degradation and affects the activities of the enzymes responsible, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Connective tissue growth factor (CTGF) expression is increased in diabetic nephropathy and is a downstream mediator of TGF-beta actions. However, whether CTGF regulates matrix degradation and the mechanism of effect in diabetes has not been reported. Human mesangial cells were cultured in media containing 5 or 25 mM glucose and, in some experiments, with recombinant human (rh)CTGF (0-1000 ng/ml) and/or appropriate neutralizing antibodies. Matrix degradation was inhibited by rhCTGF in a dose-dependent manner, and the decrease in matrix degradation caused by high glucose and by TGF-beta was significantly attenuated by addition of CTGF-neutralizing antibody (by 40.2 and 69.1%, respectively). Similar to 25 mM glucose, addition of rhCTGF increased MMP-2, TIMP-1, and TIMP-3 mRNA by 2.5-, 2.1-, and 1.6-fold, respectively (P < 0.05) but had no effect on membrane-type (MT)1-MMP or TIMP-2. Addition of TIMP-1 antibody to conditioned medium abolished the decrease in degradation caused by rhCTGF and partially prevented (by 79%) the glucose-induced inhibition of matrix degradation. In vivo studies of glomeruli from diabetic and control rats showed that intensive insulin treatment prevented the increase in expression of CTGF and TIMP-1 and attenuated the decreased matrix degradation seen in diabetes. In summary, CTGF inhibits matrix degradation by increasing TIMP-1 expression, and by this action it contributes to the inhibition of matrix breakdown by high glucose, implying that CTGF has a role in the reduced matrix degradation observed in diabetic nephropathy.
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PMID:Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: implications for diabetic nephropathy. 1534 71

The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET(A)) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET(A) receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by >50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21Cip1/WAF1. In vitro experiments blocking ET(A) receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury.
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PMID:Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. 1554 11

Atherosclerosis is characterized by inflammatory metabolic change with lipid accumulation in the artery. Atherosclerotic plaque occurs at discrete locations in the arterial system and involves the proliferation of smooth muscle cells (SMCs) together with imbalance of the extracellular matrix elements, elastic fiber in particular. The role of elastin in arterial development and disease was confirmed by generating mice that lack elastin. Thus, elastin is a critical regulatory molecule that regulates the phenotypic modulation, proliferation and migration of SMCs. We estimated that elastin expression and SMC proliferation are coupled inversely: potent stimulators of cell proliferation may potentially inhibit elastin expression and potent inhibitors of cell proliferation can stimulate elastin expression. Moreover, elastin was found to be expressed maximally at the G(0) and minimally at the G(2)/M phase during the cell cycle, suggesting that its expression is regulated by the cell growth state. The elastin peptide VPGVG enhanced SMC proliferation, resulting in the reduction of elastin expression. The inhibition of elastin expression by elastin fragments may be reflected in the negative feedback regulatory mechanism. The relationship between cell proliferation and elastin expression may be changed in atherosclerosis. Areas of atherosclerotic plaque show abnormality of elasticity and permeability from the viewpoint of the physiological function of the arterial wall. The etiology was estimated to be that cholesterol and calcium are deposited on the elastic fiber, resulting in decreased elastin synthesis and cross-linking formation. In addition, these dysfunctions of elastin fiber are also associated, in that the down-regulation of elastin and its related components (fibrillin-1 and lysyl oxidase) are directly related to calcification in SMCs. The denatured arterial elastin by cholesterol and calcium accumulation was also susceptible to proteolytic enzymes such as elastase and matrix metalloproteinase (MMP). Therefore, metabolic change in elastic fiber induces decreased elasticity and is associated with essential hypertension. Vitamin K(2) is used in drug therapy against atherosclerosis, or calcification in diabetes mellitus or dialysis, due to its promotion of the carboxylation of the matrix Gla protein.
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PMID:Atherosclerosis and matrix dystrophy. 1555 5

Cataract is a common cause of blindness and results from destruction of the microarchitecture of the lens. It is observed in many genetic syndromes, infections, inflammatory diseases and during aging. Fluctuations in lens density and light scattering by altered refraction index form the physical basis for this process, but the pathogenesis is poorly understood. Increased levels of gelatinase B/matrix metalloproteinase-9 have been reported for cataract-associated disorders such as eye inflammation and diabetes. We demonstrate that incubation of lenses with gelatinase B leads immediately to cataract. In complete eye extracts, betaB1 crystallin was identified as the major gelatinase B substrate by combination of proteomics, mass spectrometry, and Edman degradation analysis. The cleavage of betaB1 crystallin was also observed in vivo after endogenous gelatinase B-induction by the chemokine granulocyte chemotactic protein-2 in wild-type mice but not in gelatinase B-/- mice.
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PMID:Gelatinase B/matrix metalloproteinase-9 provokes cataract by cleaving lens betaB1 crystallin. 1562 92

Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.
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PMID:Effect of treatment with candesartan or enalapril on subcutaneous small artery structure in hypertensive patients with noninsulin-dependent diabetes mellitus. 1572 69

Pancreatic islet formation is a highly regulated process that is initiated at the end of gestation in rodents. Endocrine precursor cells first form within the epithelium of duct-like structures and then delaminate from the epithelium, migrate, and cluster during the early stages of islet formation. The molecular mechanisms that regulate endocrine cell migration and islet formation are not well understood. Cell culture studies suggest that matrix metalloproteinases (MMPs) 2 and 9 are required for islet formation. To address whether MMP2 and MMP9 function are essential for endocrine cell migration and islet formation in vivo, we analyzed pancreas development in MMP2/MMP9 double-deficient mice. Our results show that islet architecture and function are unperturbed in these knockout mice, demonstrating that both MMP2 and MMP9 functions are dispensable for islet formation and endocrine cell differentiation. Our studies also show that a number of other MMPs are expressed at the time islet formation is initiated. This observation suggests that other MMPs may substitute for MMP2 and MMP9 loss in pancreatic tissue. However, islet formation is unaffected in transgenic mice with modified tissue inhibitor of metalloproteinase-1 (TIMP1) levels, suggesting that MMP activity may contribute little to islet morphogenesis in vivo.
Diabetes 2005 Mar
PMID:Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo. 1573 45


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