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

Membrane-type matrix metalloproteinases (MT-MMPs) have been shown to activate pro-MMP-2 on the cell surface and are suggested to be key enzymes in tissue remodelling under various physiological and pathological conditions. To investigate the role of MT-MMP in progressive renal injury, the gene expression and enzymatic activity of MT-MMP were examined in crescentic glomerulonephritis induced by anti-glomerular basement membrane (GBM) antibody in WKY rats. Isolated glomeruli were subjected to RNA and protein extraction 0, 1, 3, 7, 14, and 28 days after intravenous injection of rabbit anti-GBM antibody. Semiquantitative RT-PCR analysis revealed that among the three members of the MT-MMP family, mRNA expression of MT2-MMP remained unchanged and that of MT3-MMP was not observed in glomeruli during the development of nephritis. However, MT1-MMP gene expression increased from day 3 and reached maximum levels at day 7 (5.5+/-0.7-fold increase over day 0), closely associated with macrophage accumulation, crescent formation, and increased proteinuria. Gelatin zymography showed that the active from of MMP-2 emerged from day 7 and remained during the experimental period accompanied by increased proMMP-2, while no active form of MMP-2 was found in control rats. Using an antisense cRNA probe, intense signals of MT1-MMP mRNA were observed mostly in cells within the crescent and in some cells in the mesangial areas. Most of these cells were ED-1-positive macrophages, based on immunostaining of sequential sections. These results suggested that in the MT-MMP family, MT1-MMP was induced in infiltrating macrophages during the development of crescentic glomerulonephritis and possibly contributed to pathological degradation of glomerular extracellular matrices through the activation of proMMP-2.
 ...
PMID:Macrophage-derived MT1-MMP and increased MMP-2 activity are associated with glomerular damage in crescentic glomerulonephritis. 1087 52

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.
 ...
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.
 ...
PMID:The activity of collagen-degrading enzymes of Wharton's jelly in EPH gestosis (pre-eclampsia). 1158 83

The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.
 ...
PMID:A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in spontaneously hypertensive rats. 1605 97

This study examined the effects of two new selective metalloprotease (MMP) inhibitors, XL081 and XL784, on the development of renal injury in rat models of hypertension, Dahl salt-sensitive (Dahl S) and type 2 diabetic nephropathy (T2DN). Protein excretion rose from 20 to 120 mg/day in Dahl S rats fed a high-salt diet (8.0% NaCl) for 4 wk to induce hypertension. Chronic treatment with XL081 markedly reduced proteinuria and glomerulosclerosis, but it also attenuated the development of hypertension. To determine whether an MMP inhibitor could oppose the progression of renal damage in the absence of changes in blood pressure, Dahl S rats were fed a high-salt diet (4.0% NaCl) for 5 wks to induce renal injury and then were treated with the more potent and bioavailable MMP inhibitor XL784 either given alone or in combination with lisinopril and losartan. Treatment with XL784 or the ANG II blockers reduced proteinuria and glomerulosclerosis by ~30% and had no effect on blood pressure. Proteinuria fell from 150 to 30 mg/day in the rats receiving both XL784 and the ANG II blockers, and the degree of renal injury fell to levels seen in normotensive Dahl S rats maintained from birth on a low-salt diet. In other studies, albumin excretion rose from 125 to >200 mg/day over a 4-mo period in 12-mo-old uninephrectomized T2DN rats. In contrast, albumin excretion fell by >50% in T2DN rats treated with XL784, lisinopril, or combined therapy. XL784 reduced the degree of glomerulosclerosis in the T2DN rats to a greater extent than lisinopril, and combined therapy was more effective than either drug alone. These results indicate that chronic administration of a selective MMP inhibitor delays the progression, and may even reverse hypertension and diabetic nephropathy.
 ...
PMID:Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. 2122 13

Most patients with chronic kidney disease (CKD) present with proteinuria and extracellular matrix (ECM) deposition in the interstitium. Matrix metalloproteinase-2 (MMP-2) is important for maintaining ECM metabolism and it affects the formation and development of CKD. Autophagy has been reported to be protective against renal tubular injury, but the role of autophagy related to ECM metabolism is unclear. Rab7 is a shared molecule of endocytosis and autophagy. The aim of this study is to explore the role of autophagy in regulating MMP-2 activity and to determine whether Rab7 functions in regulating MMP-2 activity and injury in albumin-overloaded TECs. In this study, abovine serum albumin (BSA)-overload rat model was first established and collagen deposition and deficient autophagic response were observed in vivo, and stimulation with albumin nanoparticles resulted in MMP-2 overactivation and obstructed autophagic flux induced by lysosomal dysfunction in vitro. Furthermore, overactivation of MMP-2 was mediated by its related regulatory molecules such as membrane-type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) on the membrane of TECs (HK-2 cellline). After up-regulating Rab7, albumin-induced MMP-2 overactivation was attenuated, which was reversed by chloroquine (CQ; an endocytosis inhibitor). In addition, our data indicated that up-regulation of Rab7 relieved epithelial-mesenchymal transition (EMT) and apoptosis in albumin-treated TECs. Taken together, our study demonstrated that autophagy regulates MMP-2 activity in a Rab7-dependent manner. Thus, Rab7 is a newly developed target for protecting TECs from albumin-induced injury.
 ...
PMID:Rab7 empowers renal tubular epithelial cells with autophagy-mediated protection against albumin-induced injury. 2993 81

Obesity is characterized by enhanced MR (mineralocorticoid receptor) activation, vascular stiffness, and associated cardiovascular and kidney disease. Consumption of a Western-style diet (WD), high in saturated fat and refined carbohydrates, by female mice, leads to obesity and vascular stiffening. Use of ECMR (endothelial cell-specific MR) knockout mice supports that ECMR activation is critical for development of vascular and cardiac fibrosis and stiffening. However, the role of ECMR activation in kidney inflammation and fibrosis remains unknown. We hypothesized that cell-specific deletion of ECMR would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Four-week-old female ECMR KO and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding increased body weight and fat mass, proteinuria, as well as vascular stiffness indices (pulse wave velocity and kidney artery stiffening) and impaired endothelial-dependent vasodilatation without blood pressure changes. The WD-induced kidney arterial stiffening was associated with attenuated eNOS (endothelial NO synthase) activation, increased oxidative stress, proinflammatory immune responses, alterations in extracellular matrix degradation pathways, and fibrosis. ECMR deletion prevented these abnormalities by improving eNOS activation and reducing macrophage proinflammatory M1 polarization, expression of TG2 (transglutaminase 2), and MMP (matrix metalloproteinase)-9. Our data support the concept that ECMR activation contributes to endothelial dysfunction, increased kidney artery fibrosis/stiffening, and impaired NOS (NO synthase) activation, processes associated with macrophage infiltration and polarization, inflammation, and oxidative stress, collectively resulting in tubulointerstitial fibrosis in females consuming a WD.
 ...
PMID:Diet-Induced Obesity Promotes Kidney Endothelial Stiffening and Fibrosis Dependent on the Endothelial Mineralocorticoid Receptor. 3082 47