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)

Long-term effects of urokinase on the preservation of renal function in patients with diabetic nephropathy were evaluated. Twenty-nine adult patients with non-insulin-dependent diabetes mellitus and overt proteinuria were randomly divided into two groups. One group was treated with daily oral administration of dipyridamole or dilazep dihydrochloride and weekly intravenous administration of urokinase; the other group was treated with dipyridamole alone. There was a significant decrease in the amount of proteinuria in the first group after 3 months of the treatment compared with the second group. There was also a significant preservation of renal function in the first group after three years of treatment compared with the second group. It was concluded that continuous administration of urokinase in addition to antiplatelet agents is useful in the treatment of patients with diabetic nephropathy.
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PMID:Effect of urokinase on preservation of renal function in patients with diabetic nephropathy. 177 66

Urokinase (u-PA) dissolves and removes fibrin deposits in the renal secretory pathways in various renal diseases. During pregnancy nephropathy creates a problem in preeclampsia and diabetes, but the underlying mechanism of glomerular damage is different. Preeclamptic nephropathy is characterized as 'glomerular endotheliosis' with hypertrophy of the intracapillary cells, and diabetic nephropathy as 'glomerulosclerosis' with hyaline deposits. The role of fibrin deposition for the etiology of renal damage in preeclampsia is controversial. Changes of the urinary secretion of u-PA may reflect the type of glomerular damage. Our hypotheses were that renal insufficiency is associated with a low u-PA activity in both conditions, and that severe disease is parallel to declining concentrations of u-PA. We compared the glomerular filtration rate, S-Creatinine and S-Urate with urinary u-PA excretion in 24 hypertensive and 20 diabetic pregnant women. In diabetic patients, a low u-PA concentrations was associated with an impaired renal function. In hypertensive pregnancy, the u-PA excretion did not reflect the severity of the hypertensive disease or renal function. No association was found between u-PA excretion and renal function post partum in any group. We conclude that renal urokinase activity plays a role for renal function in diabetic but not in hypertensive pregnancy.
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PMID:Renal function and urinary urokinase in hypertensive and diabetic pregnancies. 782 57

To elucidate a role of tPA, uPA and PAI-1 for the development of diabetic glomerulosclerosis, the effect of high glucose concentration on the production of both basal and thrombin-mediated tPA, uPA and PAI-1 antigens from human mesangial cells was investigated. The culture of mesangial cells in the presence of high glucose (33 mM) for 11 days resulted in an increase in the synthesis of tPA and uPA when compared with that in normal glucose concentration (5 mM). In contrast, the cells grown in high glucose produced less PAI-1 than those in normal glucose. Thrombin stimulated dose-dependently the production of tPA, uPA and PAI-1 from the cells grown in either 5 or 33 mM glucose. However, the magnitude of the increase in tPA, uPA and PAI-1 from the cells grown in high glucose was less than that in normal glucose. These results suggest that the plasmin activity in mesangial cells may increase under a high glucose condition, leading to increased proteolysis of mesangial matrix. In addition, either fibrinolysis or proteolysis mediated by thrombin may be altered by high glucose concentration. Therefore, it is postulated that the turnover of mesangial matrix may be increased in diabetic nephropathy.
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PMID:A high concentration of glucose alters the production of tPA, uPA and PAI-1 antigens from human mesangial cells. 792 84

Mesangium enlargement is a central feature of diabetic nephropathy and almost certainly plays a pathogenic role in this condition. Previous studies have shown that mesangium degradation is reduced in a high glucose mileau. Plasmin has been shown to play an important role in extracellular matrix degradation, both directly and through its ability to activate the matrix metalloproteinases. We therefore investigated how high glucose concentration may affect the various components of the plasminogen cascade on mesangial cells and whether it impairs the ability of the mesangial cell to generate plasmin activity. Result showed decreased binding of plasminogen and the urokinase type plasminogen activator to the mesangial cell surface while the tissue type plasminogen activator and the plasminogen activator-1 associated with mesangial cells were increased. The net effect of these changes was a reduced capacity of mesangial cell layers to generate plasmin activity in a high glucose environment. We postulate that this may be of importance in the reduced mesangium degradation which occurs in diabetes.
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PMID:High glucose reduces generation of plasmin activity by mesangial cells. 914 50

Decreased degradation of the glomerular extracellular matrix (ECM) is thought to contribute to the accumulation of glomerular ECM that occurs in diabetic nephropathy and other chronic renal diseases. Several lines of evidence indicate a key role for the plasminogen activator/plasminogen/plasmin system in glomerular ECM degradation. However, which of the two plasminogen activators (PAs) present in renal tissue, tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA), is responsible for plasmin generation and those factors that modulate the activity of this system remain unclear. This study utilized mesangial cells isolated from mice with gene deletions for tPA, uPA, and plasminogen activator inhibitor 1 (PAI-1) to further delineate the role of the PA/plasminogen/plasmin system in ECM accumulation. ECM degradation by uPA-null mesangial cells was not significantly different from controls (92% +/- 1%, n = 12). In contrast, ECM degradation by tPA-null mesangial cells was markedly reduced (-78 +/- 1%, n = 12, P < 0.05) compared with controls, whereas tPA/uPA double-null mesangial cells degraded virtually no ECM. Previous studies from this laboratory have established that transforming growth factor-beta1 (TGFbeta1) inhibits ECM degradation by cultured mesangial cells by increasing the production of PAI-1, the major physiological PA inhibitor. In keeping with this observation, TGFbeta1 (1 ng/ml) had no effect on ECM degradation by PAI-1-null MC. High glucose levels (30 mM) in the presence or absence of insulin (0.1 mM) caused a moderate increase in ECM degradation by normal human mesangial cells. In contrast, glycated albumin, whose concentration is known to increase in diabetes, produced a dose-dependent (0.2-0.5 mg/ml) inhibition of ECM degradation by normal human mesangial cells. Taken together, these results document the importance of tPA versus uPA in renal plasmin production and indicate that in contrast to elevated glucose, glycated albumin may contribute to ECM accumulation in diabetic nephropathy.
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PMID:Extracellular matrix degradation by cultured mesangial cells: mediators and modulators. 1453 May 9

Plasmin is an important factor in the degradation of extracellular matrix. In the study reported here we examined the expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), and uPA receptor (uPAR), as well as the relevance of such expression to the production of type IV collagen, a major component of extracellular matrix, in the renal tissue of rats with streptozotocin-induced diabetes. Because angiotensin II is involved in the synthesis of PAI-1 and uPA, we also examined the effect of benazepril, an angiotensin-converting-enzyme inhibitor, on the expression of PAI-1, uPA, and uPAR messenger RNAs (mRNAs) and type IV collagen protein. Rats with streptozocin-induced diabetes-some untreated and some treated with 30 mg/L benazepril-and nondiabetic control rats were sacrificed at 4, 12, or 24 weeks after induction of diabetes. We examined the expression of PAI-1, uPA, and uPAR mRNAs through the use of in situ hybridization and that of type IV collagen by means of immunohistochemical methods. In control rats, we detected weak signals for PAI-1, uPA, and uPAR mRNAs in glomeruli. Diabetic rats exhibited high levels of expression of PAI-1, uPA, and uPAR mRNAs and type IV collagen protein, mainly in mesangial cells. These mRNAs were synthesized in various renal cells (epithelial, mesangial, and endothelial cells and Bowman's capsule). Benazepril inhibited increases in all 3 mRNAs, especially in the mesangium; reduced type IV collagen expression; and attenuated mesangial expansion. Our results indicated that altered expression of PAI-1, uPA, and uPAR in diabetic nephropathy was associated with mesangial expansion and that the beneficial effects of ACE-I may be at least associated with such expression.
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PMID:Renal synthesis of urokinase type-plasminogen activator, its receptor, and plasminogen activator inhibitor-1 in diabetic nephropathy in rats: modulation by angiotensin-converting-enzyme inhibitor. 1532 1

Chronic kidney disease (CKD) is common in China. In residents older than 40 years in Beijing, China, 11.3% of subjects had at least one indicator of kidney damage. The primary cause of chronic renal failure in China was glomerulonephritis, which was followed by diabetic nephropathy and hypertensive nephrosclerosis. Renal failure, cardiovascular disease and infection were important complications. IgA nephropathy (IgAN) is the most common CKD in China. The prevalence of hypertension, intrarenal artery lesions and tubulointerstitial lesions in patients with IgAN at the time of renal biopsy was approximately 40, 55 and 85%, respectively. The genetic variation in Megsin confers susceptibility to IgAN in Chinese. The patients with SL/LL genotypes of the MUC20 gene, the 38AA genotype of uteroglobin and DD genotype of the angiotensin-converting enzyme gene had a higher risk of progression. Chinese prospective clinical trials showed that benazepril (BZ) conferred substantial renal benefits in patients with advanced renal insufficiency. The combined therapy with urokinase and BZ was more effective than with BZ alone in reducing proteinuria and protecting renal function in Chinese patients with severe IgAN. Lupus nephritis (LN) is a common form of secondary renal disease diagnosed by renal biopsy in China. Chinese multicenter clinical trials showed that mycophenolate mofetil or leflunomide combined with steroids was effective as induction therapy for proliferative LN.
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PMID:Epidemiology, major outcomes, risk factors, prevention and management of chronic kidney disease in China. 1789 Aug 52

Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide-induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility.
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PMID:The role of osteopontin in the development of albuminuria. 1844 55

Deregulated apoptosis of MCs (mesangial cells) is associated with a number of kidney diseases including end-stage diabetic nephropathy. Cell death by apoptosis is a tightly orchestrated event, whose mechanisms are not completely defined. In the present study we show that the uPA (urokinase-type plasminogen activator)/uPAR (uPA receptor) system can initiate both cell survival and pro-apoptotic signals in human MCs in response to different apoptotic stimuli. uPA abrogated MC apoptosis induced by serum withdrawal conditions and enhanced apoptosis initiated in MCs by high glucose. Effects of uPA were independent of its proteolytic activity and required uPAR for both pro- and anti-apoptotic effects. Studies on the uPAR interactome provide evidence that the opposing effects of uPA were directed via different uPAR-interacting transmembrane partners. Exposure of MCs to RGD (Arg-Gly-Asp) peptide led to abrogation of the anti-apoptotic effect of uPA, which implies involvement of integrins in this process. A pro-apoptotic effect of uPA under high-glucose conditions was mediated via association of uPAR and the cation-independent M6P (mannose-6-phosphate)/IGF2R (insulin-like growth factor 2 receptor). Both receptors were co-precipitated and co-localized in MCs. Studies on the underlying signalling indicate that the ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt and BAD (Bcl-2/Bcl-X(L)-antagonist, causing cell death) protein were involved in regulation of apoptosis by uPA in MCs. M6P/IGF2R mediated BAD perinuclear localization during apoptosis initiated by uPA and high glucose. In conclusion, we provide evidence that, in MCs, the uPA/uPAR system regulates survival/apoptosis processes in a stimulus-specific fashion via a mitochondria-dependent mechanism and that BAD protein serves as a downstream molecule.
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PMID:Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus. 1856 64

In this study, we assessed the effects of shear stress on the expression of plasminogen activator(tPA and uPA) mRNA in cultured NRK-52E cells (a kidney proximal tubular epithelial cell line of normal rat origin) and investigated the mechanism of tubulointerstitial extracellular matrix (ECM) remodeling in the early stage of diabetic nephropathy (DN). The cultured NRK-52E cells were exposed to shear stress of 5 and 10 dyn/cm2 for 1, 3 and 6 hours respectively. Semi-quantity RT-PCR was used to detect the expression of tPA and uPA mRNA. Shear stress down-regulated the expression of tPA and uPA mRNA in cultured NRK-52E cells in a magnitude and time-dependent way. The results suggested that the increased tubular shear stress in the early-stage of DN could decrease the expression of tPA and uPA in renal proximal tubular cells, lead to the reduction of tubulointerstitial fibrinolytic activity and involve in the remodeling of ECM.
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PMID:[Effects of shear stress on expression of plasminogen activator (tPA and uPA) in cultured kidney proximal tubular epithelial cells and its significance]. 1916 1


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