Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amino-terminal amino acid sequence and several internal peptide sequences of angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A, kininase II; EC 3.4.15.1) purified from human kidney were used to design oligonucleotide probes. The nucleotide sequence of ACE mRNA was determined by molecular cloning of the DNA complementary to the human vascular endothelial cell ACE mRNA. The complete amino acid sequence deduced from the cDNA contains 1306 residues, beginning with a signal peptide of 29 amino acids. A highly hydrophobic sequence located near the carboxyl-terminal extremity of the molecule most likely constitutes the anchor to the plasma membrane. The sequence of ACE reveals a high degree of internal homology between two large domains, suggesting that the molecule resulted from a gene duplication. Each of these two domains contains short amino acid sequences identical to those located around critical residues of the active site of other metallopeptidases (thermolysin, neutral endopeptidase, and collagenase) and therefore bears a putative active site. Since earlier experiments suggested that a single Zn atom was bound per molecule of ACE, only one of the two domains should be catalytically active. The results of genomic DNA analysis with the cDNA probe are consistent with the presence of a single gene for ACE in the haploid human genome. Whereas the ACE gene is transcribed as a 4.3-kilobase mRNA in vascular endothelial cells, a 3.0-kilobase transcript was detected in the testis, where a shorter form of ACE is synthesized.
 ...
PMID:Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. 284

The distribution of kininases along microdissected nephron segments was studied. Single nephrons from collagenase treated rabbit kidney were microdissected and divided into following 9 segments: glomerulus; early proximal tubule; middle proximal tubule; late proximal tubule; cortical thick ascending limb; distal convoluted tubule; connecting tubule; cortical collecting tubule; medullary collecting tubule. Kininase activities in these nephron segments were measured with or without kininase II inhibitor. Kininase II and other peptidases were mainly localized in glomeruli and whole part of the proximal tubules.
 ...
PMID:Distribution of kininase activity along the rabbit nephron. 303 11

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.
 ...
PMID:Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. 891 81

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
 ...
PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II action may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells to induce sclerosis independent of its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used cell culture systems. Glucose and Ang II have been shown to produce similar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule proteinases. Glucose increases expression of the angiotensinogen gene in proximal tubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangial cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced increment in TGF-beta secretion. Taken together, these findings support the hypothesis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TGF-beta secretion, leading to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation. This may be an important mechanism linking hyperglycemia and Ang II in the pathogenesis of diabetic nephropathy.
 ...
PMID:Role of angiotensin II in diabetic nephropathy. 1099 97

Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNFalpha, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNFalpha, or combinations of TNFalpha with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNFalpha, IL-1beta, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNFalpha, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNFalpha, IL-1beta) and immunoregulatory (IL-6, IL-10) cytokines. TNFalpha stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNFalpha significantly. These results indicate that TNFalpha strongly activates the tenocytes to amplify their own TNFalpha expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear.
 ...
PMID:Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytes. 2012 72

A key role in tumor progression play two processes--the destruction and angiogenesis. Matrix metalloproteases (MMPs) play a leading role during tissue degradation. Tissue collagenase--MMP-1 and MT1-MMP hydrolyze fibrillar collagens, which are the basis of connective tissue matrix, and ensure the development of an invasive process. Gelatinase A and B (MMP-2 and MMP-9) hydrolyze collagen type IV, which is the basis of the basal membrane, and facilitate the development of metastasis. Endogenous tissue inhibitors TIMP-1 and TIMP-2 are involved in the regulation of MMP expression and activity. It has been established that MMP-9 release vascular endothelial growth factor (VEGF) associated with the STM--the primary inductor angiogenesis. Angiotensin-converting enzyme (ACE) participates in the induction of VEGF synthesis. ACE--a key enzyme of the renin-angiotensin system, forms angiotensin II, which interactes with the receptor ATIR and induces VEGF synthesis, as well as stimulates endothelial cell proliferation. Our experimental studies devoted to the study of particularity expression of key enzymes of destruction and angiogenesis in squamous cell carcinoma of the cervix (SCC). It was studied: MMP-1, MT1-MMP, MMP-2 and MMP-9 and their endogenous regulators: TIMP-1, TIMP-2, and as well as ACE. Work was performed on clinical specimens containing the tumor tissue, taking into account the presence or absence of metastasis to regional lymph nodes and the specimens of adjacent morphologically normal tissue. It was shown that the increase of MMP-1, MT1-MMP and MMP-9 expression and low of TIMP-1 and TIMP-2 expression makes the main contribution to the destructive (invasive) potential of SCC. The change of MMP-2 expression is not so significant and it is less influenced to the destructive potential. It was shown dramatic increasing of MMP-1 and MMP-9 activity in metastasizing tumor tissue ACE activity in a tumor in most of the samples was higher than the activity in normal tissues. It was established that the expression of key enzymes degradation and angiogenesis occurs not only in tumor but also in normal tissues. Data are important for understanding the mechanisms of tumor progression and have prognostic value and may affect the therapeutic strategy for patients.
 ...
PMID:[Key enzymes of degradation and angiogenesis as a factors of tumor progression in squamous cell carcinoma of the cervix]. 2589 71