Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM) in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.
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PMID:Proteinases and the glomerulus: their role in glomerular diseases. 228 May 77

Vasoactive agents alter proteinuria by modulating glomerular hemodynamics. The authors hypothesized that vasoactive agents may be altering degradation of the collagen component of glomerular basement membrane, which also may be contributing to proteinuria. Mesangial cells treated with 10(-6) M angiotensin II had higher (P < 0.01) metalloproteinase activity (MA) when compared with control cells. This effect of angiotensin II was dose dependent. Amlodipine (10(-6) M), a calcium channel blocker, inhibited MA (control, 5.86 +/- 0.08 microgram versus 4.13 +/- 0.06 microgram gelatin degraded/mg protein, P < 0.001). The decrease in mesangial MA caused by amlodipine also occurred in a dose dependent manner. Amlodipine attenuated (P < 0.05) angiotensin II-stimulated MA (control, 6.69 +/- 0.30 micrograms, angiotensin II, 10.68 +/- 0.49 micrograms, angiotensin II+amlodipine 8.29 +/- 0.30 micrograms gelatin degraded/mg protein). Prostaglandin E2 increased (P < 0.001) MA (control, 10.22 +/- 0.9 micrograms versus prostaglandin E2, 17.9 +/- 0.9 micrograms gelatin degraded/mg protein), whereas indomethacin, a prostaglandin inhibitor, attenuated the metalloproteinase activity (control, 9.67 +/- 0.32 micrograms vs. 10(-6) M indomethacin, 4.22 +/- 0.31 micrograms gelatin degraded/mg protein, P < 0.001). Indomethacin also inhibited angiotensin II-stimulated MA (angiotensin II, 18.66 +/- 0.46 vs. angiotensin II+indomethacin, 11.86 +/- 0.56 micrograms degraded/mg protein, P < 0.001). Similarly, meclofenamate, another prostaglandin inhibitor, attenuated (P < 0.001) angiotensin II-induced MA. Because angiotensin II increases prostaglandin E2 synthesis by mesangial cells, it appears that increased MA, induced by angiotensin II, may be mediated partly through the generation of prostaglandin E2.
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PMID:Vasoactive agents modulate matrix metalloproteinase-2 activity by mesangial cells. 750 3

The present study was designed to assess whether a specific endothelin A (ETA) receptor antagonist, FR139317, affects the progression of lupus nephritis and affects transcription of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP)-1, and accumulation of ECM proteins in the renal cortex of NZB/W F1 mice. mRNA levels for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-1, -2, -3, and TIMP-1 increased significantly as nephritis progressed in NZB/W F1 mice. At 48 weeks of age, the levels of mRNA for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, HSPG, MMP-1, -2, -3, and TIMP-1 were increased by 5.6- (P < 0.001), 3.6- (P < 0.01), 6.8- (P < 0.001), 5.2- (P < 0.001), 5.0- (P < 0.001), 6.0- (P < 0.001), 7.6- (P < 0.001), 4.2- (P < 0.01), 8.2- (P < 0.001), and 15.2-fold (P < 0.001), respectively, in the renal cortex of NZB/W F1 mice compared to NZW mice. Immunofluorescence microscopy showed that the accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice increased markedly with the progression of nephritis. At 20 weeks of age, NZB/W F1 and NZW mice were divided into two groups that received either FR139317 or its vehicle (saline) intraperitoneally, daily, for 28 weeks. The development of histological lesions, proteinuria, hypertension, accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice were suppressed by FR139317 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a specific endothelin A receptor antagonist on murine lupus nephritis. 772 34

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

Experimental studies indicate that Angll is involved in the process of tissue destruction in chronic renal diseases. This notion has been verified in a number of small-to large-scale clinical studies using angiotensin (ANG) I converting enzyme inhibitors (ACEI). Although the repertoire of the pathophysiologic cascade underlying the progressive destruction of renal tissue has continued to expand over recent years, from proteinuria and physical forces to growth factors and metalloproteinase disregulations, studies now suggest that Angll is involved in many, if not all, of these processes. Because these expanded pathophysiologic potentials of Angll are based primarily on observations in vitro, their significance in vivo, and in humans in particular, needs to be established. Recent studies in animals and humans indicate that the role of Angll in renal tissue destruction is subject to the modulation of multiple environmental and genetic factors, such as dietary habit and ACE genotype. Further delineation of the role of Angll in this respect for specific renal diseases and patients will enable us to design an efficient therapeutic intervention for this otherwise most complex problem of today's nephrology.
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PMID:Angiotensin in progressive renal diseases: theory and practice. 891 63

We and others have already reported that Onpi-to (TJ-8117), a Kampo medicine composed mainly of Rhei Rhizoma, has a beneficial effect on an adenine-induced renal failure model and 5/6 nephrectomized renal failure. However, little is known about the detailed mechanism of this medicine when used for renal failure. The present study was designed to clarify whether or not TJ-8117 affects TGF-beta 1 production or activation in glomeruli of 5/6 nephrectomized rats. TJ-8117 (400 mg/kg/ day) and captopril (50 mg/kg/day) were administered as drinking water from the day immediately after the operation and continued throughout the experiment. All rats were sacrificed at 4 weeks and renal cortical tissue was removed to quantify the protein and activity of TGF-beta 1 and activities of metalloproteinase. TIMP expression and extracellular matrix (collagen type I, IV) in the glomeruli were analysed histologically. TJ-8117 inhibited proteinuria, and the accumulation of collagen type I and IV in glomeruli of nephrectomized rats. In addition, TJ-8117 inhibited the TGF-beta 1 positive area in the glomeruli and the elevation of mature TGF-beta 1 level in the renal cortex of nephrectomized rats. In the TJ-8117 treated group, activities of metalloproteinase 1, 2 or 9 in the renal cortex were elevated compared with the control group. Captopril failed to affect the TGF-beta 1 level. We also found that the constitutive herbs in TJ-8117, Rhei Rhizoma and Ginseng radix, inhibited the process from inactive TGF-beta 1 to mature TGF-beta 1.
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PMID:[Effect of Onpi-to (TJ-8117) on TGF-beta 1 in rats with 5/6 nephrectomized chronic renal failure]. 895 1

Renal remodelling in hyperinsulinic/insulinopenic states is mediated by glucotoxicity, endothelial dysfunction and vascular and nephron collagen turnover. Hypertensive and renal links are renewed by renoprotective interventions of renin-angiotensin. Vasoactive peptide processing and vascular collagen deposition are under the tight control of two zinc metalloproteinase families that regulate vascular tone and trophicity: gluzincins (or vasopeptidases) are convertases of angiotensins, endothelins or atrial natriuretic factors; and metzincins or matrix metalloproteases (MMP, matrixins)] regulate vascular type IV collagen basement membrane proteolysis. Association of natural tissue inhibitors of MMPs, pharmacological inhibitors of vasopeptidases [either conventional (angiotensin-converting enzyme inhibitors) or innovative (omapatrilat)], together with synthetic MMP inhibitors, are currently screened to counteract vascular remodelling and renal scarring. Our studies focused on the 72 kDa (MMP-2) and 92 kDa (MMP-9) matrixin gelatinases and tissue inhibitors involved in basement membrane degradation and rebuilding. Three complementary settings were developed, allowing evaluations from basic to clinical stages. A leucocyte-endothelial transmigration model was designed for transcription and addressing of enzymes and inhibitors, in situ matrix degradation, and blockading by metalloprotease inhibitors (captopril). Insulin-resistant fructose-fed rats showed heavy proteinuria and glomerulosclerosis involving angiotensin II-dependent changes in renal gelatinases and inhibitors. Urinary gelatinolytic profiles from Type 2 diabetic patients with overt nephropathy were compared with those of normal first-degree relatives and age-matched healthy controls. Physiologically, MMP-9 was the primary urinary gelatinolytic enzyme. In Type 2 diabetic proteinuric patients, MMP-9 and MMP-2 releases were significantly increased in the absence of renin-angiotensin blockade, while first-degree relatives showed reduced gelatinase levels suggestive of a genetic control of renal matrix regulation prior to potential glycaemic dysregulation. These preliminary data suggest that local MMP/TIMP imbalance is involved in diabetic renal remodelling. Further studies are needed to define the redundancies and specificities of vasopeptidase and MMP inhibitors, differentiate the antihypertensive effect from target-organ protection, screen for innovative pharmacological compounds, and validate simple, efficient biological markers of renal fibrosis progression and the effect of anti-fibrotic therapeutic interventions.
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PMID:Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions. 1092 70

Oedema/proteinuria/hypertension (EPH) gestosis is one of the more common complications observed during pregnancy. Our previous studies demonstrated some qualitative and quantitative changes in the extracellular matrix of Wharton's jelly in newborns delivered by mothers with EPH gestosis. For this reason it was decided to evaluate the effect of EPH gestosis on the activity of gelatinolytic and proteolytic enzymes which may be involved in collagen degradation in Wharton's jelly. Zymographic analysis of control and EPH gestosis samples of Wharton's jelly demonstrates different electrophoretic patterns of gelatinolytic enzymes. The control Wharton's jelly contains two latent forms of gelatinolytic enzymes: gelatinase A [metalloproteinase (MMP)-2, 72 kD] and gelatinase B (MMP-9, 92 kD). In contrast to control tissue, the main gelatinolytic enzyme of EPH gestosis Wharton's jelly is gelatinase A (MMP-2). It was found that the proteolytic activity in EPH gestosis Wharton's jelly differs from control. The decrease in gelatinase activity may be one of the factors which promote the accumulation of collagen in this tissue.
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PMID:The activity of collagen-degrading enzymes of Wharton's jelly in EPH gestosis (pre-eclampsia). 1158 83

Treatment options for crescentic glomerulonephritis include the use of steroids, cytotoxic therapy, and, in severe cases, intravenous immunoglobulins and plasmapheresis. Injury and lysis of capillary glomerular basement membrane, which is made up of type IV collagen, laminin, fibronectin, and proteoglycans, by serine proteinases and matrix metalloproteinases (MMPs) likely is an important participant in the pathogenesis of crescentic glomerulonephritis. Tetracycline derivatives inhibit not only the activity of MMPs, but also their production, and have been investigated for the treatment of disorders in which the MMP system becomes amplified, such as degenerative osteoarthritis, periodontitis, cancer, and abdominal aortic aneurysm. We report an interesting case of crescentic glomerulonephritis in a young man who was treated with cyclophosphamide and prednisone. The patient developed steroid-induced acne that was treated with long-term oral doxycycline therapy. During the period the patient was administered doxycycline, proteinuria decreased by 70% and recurred when doxycycline was stopped. To our knowledge, this is the first report of possible benefits of a metalloproteinase inhibitor (doxycycline) in glomerulonephritis in humans. Future studies are urgently required to explore the option of metalloproteinase inhibitors in the treatment of proliferative glomerulonephritis.
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PMID:Doxycycline decreases proteinuria in glomerulonephritis. 1290 Aug 22


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