Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extrarenal renin has been a subject of considerable interest. Chiefly, studies have focused on brain and vascular renin activity in large arteries. A method now exists for the isolation from the cerebrum of microvascular tissues consisting of arterioles, capillaries and venules. The present study has demonstrated reninlike enzymatic activity within the cerebral microvasculature of the rat that is distinct from plasma renin activity. Maximal activity was observed at pH 4.5 with no measurable activity at pH 7.4. Activity with homologous renin substrate was only 13% of that measured with hog substrate whereas a 400-fold increase in reninlike specific activity was observed when microvessel homogenates were incubated with synthetic tetradecapeptide renin substrate. Bilateral nephrectomy did not affect microvascular reninlike activity. Pepstatin 15 nM, abolished reninlike activity in microvessel homogenates. Mean specific microvessel reninlike activity was 1.15 +/- 0.20 pg angiotensin I . microgram protein-1 . h-1 in control animals. Neither sodium depletion nor DOC-saline administrations caused a significant change in microvascular reninlike activity. It is suggested that the reninlike activity observed in microvessels is an acid protease, perhaps cathepsin D derived from lysosomes.
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PMID:Reninlike enzymatic activity in the cerebral microvessels of the rat. 698 71

The ultrastructural cytochemical reactivity, renin activity, and cathepsin D activity of atria and ventricle of the bullfrog have been assessed. The specific granules (A, B, and D) were found to be argentaphobic when ultrathin sections of Araldite-embedded atria and ventricle were stained according to the periodic acid-thiocarbohydrazide-silver proteinate technique of Thiery. The entire core of the specific granules was moderated positive after ultrathin sections of glutaraldehyde-fixed, glycol methacrylate embedded atria and ventricle were stained by phosphotungstic acid at a low pH. A similar reaction was shown by the cell coat, intercalated discs, residual bodies (C granules), and Z discs as well as by a very small portion of the Golgi complex. Incubation of ultrathin sections of atria and ventricule fixed only in glutaraldehyde and embedded in glycol methacrylate with either pronase or trypsin resulted in selective digestion of specific granules and Z discs and, to a much lesser degree, of the cell coat. As cathepsin D activity and renin activity were present in both atria and ventricle, the generation of angiotensin I by these cardiocytes might have been due to either enzyme. Nevertheless, because of the glycoprotein nature of specific granules and of the endocrinelike ultrastructure of atrial and ventricular cardiocytes in the frog, the present results raise the possibility that specific granules may contain renin.
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PMID:Ultrastructural cytochemistry of atrial and ventricular cardiocytes of the bullfrog (Rana catesbeiana). Relationship of specific granules with reninlike activity of the myocardium. 701 73

Mouse brain renin and kidney renin were purified by a 3-step procedure: acetone powder extraction. Sephadex G-100 chromatography, and blue agarose affinity chromatography. The latter efficiently separated from cathepsin D-like acid protease activity. Mouse brain renin had an optimum of enzyme activity of pH 7.0. This differed from mouse kidney renin, which had an optimum at pH 8.5. In vitro, brain renin formed angiotensin I from rat plasma angiotensinogen and had no angiotensinase activity. Mouse brain renin was inhibited by monospecific antibodies raised against pure mouse submandibular gland renin. In vivo activity of the enzyme was tested by injection of brain renin into the lateral brain ventricle of rats. This resulted in the formation of angiotensin I from endogenous brain angiotensinogen, in the stimulation of water uptake, and in a long-lasting increase of arterial blood pressure. The latter could be blocked by the competitive angiotensin II receptor antagonist, saralasin. The results showed that brain renin is active under physiological conditions.
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PMID:In vivo activity of purified mouse brain renin. 702 Aug 79

The dipsogenic activity of two artificial renin substrates, tetradecapeptide and tridecapeptide, was studied. The dose-response curves obtained with these peptides, following intracerebroventricular administration, were similar to that of angiotensin I. The angiotensin II antagonist, Sar1, Ala8-angiotensin II, inhibited the dipsogenic effect of tetradecapeptide, indicating the conversion of the latter peptide into angiotensin II. The lower dipsogenic activity of tridecapeptide points to a conversion of this renin substrate into angiotensin III. Specific inhibition of tetradecapeptide induced drinking by the endopeptidase inhibitor N-acetyl-pepstatin suggests the involvement of an endopeptidase in the conversion of the renin substrates in the brain. Two endopeptidases present in the brain (cathepsin D and renin), were compared with respect to their capacity to generate angiotensin I from artificial renin substrate in vitro. Cathepsin D was active under only acidic pH conditions, whereas renin showed a wider pH range with maximal activity in the non-acidic region. Moreover, cathepsin D did not generate angiotensin I from natural, cerebrospinal fluid-angiotensinogen in vitro, and lacked dipsogenic activity following central administration. Small amounts of renin, however, were able to release angiotensin I from cerebrospinal fluid in vitro. In addition, this enzyme induced high dipsogenic activity upon intracerebroventricular injection. These results support the existence of a functionally active central renin-angiotensin system and provide an argument against the involvement of cathepsin D in the formation of angiotensin I in the brain.
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PMID:Angiotensin generation in the brain and drinking: indications for the involvement of endopeptidase activity distinct from cathepsin D. 702 65

The generation of angiotensin I from the artificial renin substrate tetradecapeptide by proteolytic enzymes in rat brain tissue was studied. The involvement of endopeptidase activity in the enzymatical cleavage of the renin substrate was inferred from the simultaneous accumulation of both angiotensin I and the complementary tetrapeptide Leu-Val-Tyr-Ser on incubation of tetradecapeptide with rat brain tissue. This endopeptidase activity was active over a pH range of 3.5--7.5. In contrast, cathepsin D released angiotensin I from tetradecapeptide only at acidic pH. The angiotensin I accumulation on incubation of tetradecapeptide with brain endopeptidase activity was only partly inhibited in the presence of an excess of the carboxyl protease inhibitor N-acetyl pepstatin. Further, the brain endopeptidase activity displayed a subcellular localization different from that of acid protease activity. It is concluded that angiotensin I can be generated in the brain by soluble endopeptidases, which are distinct from cathepsin D.
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PMID:Subcellular localization in rat brain of angiotensin I-generating endopeptidase activity distinct from cathepsin D. 703 49

Anesthetized cats were infused with angiotensin II or its vehicle (0.05 M phosphate buffer) to detect actions of angiotensin II which can contribute to shock. Mild hemorrhage, or saralasin-induced angiotensin II receptor blockade, were also employed in an attempt to enhance or reduce the angiotensin II effects. Angiotensin II produced a prolonged reduction in superior mesenteric artery blood flow (50% of initial) and an elevation in plasma lysosomal hydrolase (cathepsin D) activity. Additionally, angiotensin II disrupted the normal functioning of the coronary endothelium resulting in macroscopically visible hemorrhagic patches on the myocardium. Saralasin blockade of the angiotensin II receptor prevented the pressor, splanchnic vasoconstrictor, and lysosomal labilizing actions of angiotensin, and also decreased the incidence of cardiac hemorrhages. Angiotensin II infusion after bleeding to 80 mm Hg, however, increased lysosomal hydrolase release, indicating an exacerbation of angiotensin II effects. These data indicate that high levels of angiotensin II are capable of inducing alterations similar to those occurring in hemorrhagic shock. These deleterious effects of angiotensin II were abolished by saralasin and potentiated by a mild hemorrhage.
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PMID:Shock potentiating actions of angiotensin II infusion in cats. 744 49

This report describes the pharmacological properties of a novel renin inhibitor (YM-26365: (3R)-3-[3-[(1S)-1-cyclohexylmethyl-2-hydroxy-3- [(1-methyl-5-tetrazolyl)thio]propyl]ureido]-1-methyl-5-phenyl- 2,3-dihydro-1H-1,4-benzodiazepin-2-one) with molecular weight 577 and no peptide bonds. YM-26365 inhibited human plasma renin with an IC50 value of 2.9 x 10(-6) M, but did not affect plasma renin from dogs, rabbits, and rats at 10(-4) M. YM-26365 inhibited not only human renin, but also cathepsin D with an IC50 value of 1.7 x 10(-5) M. This compound competitively inhibited the reaction between recombinant human renin and N-acetyl tetradecapeptide with a Ki value of 1.1 x 10(-6) M. In pithed spontaneously hypertensive rats, YM-26365 at 10 mg/kg i.v. significantly antagonized the pressor response to recombinant human renin, but did not affect responses to angiotensin II, angiotensin I, norepinephrine, or arginine vasopressin. Similarly, oral administration of YM-26365 (10 and 30 mg/kg) to pithed spontaneously hypertensive rats caused a shift to the right of the recombinant human renin dose-pressor response curve. Systemic bioavailability as determined on the basis of the ratio of the total area under the plasma concentration-time curve after 3 mg/kg i.v. and 30 mg/kg orally to rats was 9.6%. These results demonstrate that YM-26365 is a weak but orally absorbed, low molecular weight renin inhibitor.
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PMID:Pharmacological properties of YM-26365, a low molecular weight, orally active renin inhibitor. 770 34

The structure of rabbit procathepsin E was determined by molecular cloning of its cDNA. The proenzyme consisted of 379 amino acids and had structural features common to human and guinea-pig procathepsin E species. The highly conserved tripeptide sequence at the active site of aspartic proteinases, Asp-Thr(Ser)-Gly, is, however, replaced by Asp-Thr-Val in rabbit procathepsin E. To our knowledge, this is the first case of such a variation in aspartic proteinases. The processed form, cathepsin E, hydrolyzed various biologically active peptides maximally at around pH5. Tachykinins, such as substance P and neurokinin A, were hydrolyzed most rapidly, with specific cleavage of sequences essential for their activity. The rates of hydrolysis were several hundred-fold higher than those of cathepsin D. Furthermore, cathepsin E was able to inactivate a functional-domain peptide of fibroblast growth factor, the sequence of which resembles those of tachykinins, and it was active in the generation of functional peptides, such as endothelin and angiotensin I, from their respective precursors. Procathepsin E was detected at high levels in various fetal tissues, such as the liver, stomach and blood cells. At the adult stage, the proenzyme was detectable only in specific tissues, such as the urinary bladder, duodenum and colon. Northern-blot analysis showed similar stage-specific and tissue-specific expression of the mRNA for procathepsin E. Since tachykinins and other suited peptide substrates of cathepsin E have been shown to have mitogenic activity, (pro)cathepsin E may regulate the growth and differentiation of embryonic and fetal tissues by degrading or processing these peptides. The enzyme may also regulate the physiological activities of adult tissues which are mediated by substance P and related tachykinins.
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PMID:Rabbit procathepsin E and cathepsin E. Nucleotide sequence of cDNA, hydrolytic specificity for biologically active peptides and gene expression during development. 840 90

Chorionic trophoblast, decidual cells, and macrophages have all been named as the site of renin in the placental membranes. To establish more clearly the nature of the renin-containing cells in the placental membranes, double immunostaining techniques were used to stain renin and specific cell markers in the same tissue sections. Cytokeratin was selected as an ectodermal cell marker and CD68 as a cytoplasmic macrophage marker. Cross-binding between antibodies was prevented by blocking species-related binding sites between the first and second sequence of the double-immunostaining procedures and by using highly selective immunostaining techniques in the second sequence. The results clearly show renin immunostaining in CD68-positive macrophages and not in cytokeratin-positive trophoblast. The anti-renal renin monoclonal antibody showed high affinity cross-reactivity with cathepsin D, another aspartic proteinase that can release angiotensin I from angiotensinogen. This should be seen in the context of earlier findings that only two of four anti-renal renin monoclonal antibodies showed staining in uterine and placental tissues and both cross-reacted with cathepsin D. The results indicate that differentiation between renin and cathepsin D and, possibly, other substances with shared properties and epitope homology deserves more attention than it has received thus far.
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PMID:Identification of 'renin'-containing cells in the choriodecidua. 857 May 73

Scar tissue found at the site of myocardial infarction (MI) contains phenotypically transformed fibroblast-like cells termed myofibroblasts (myoFb). In injured cardiac tissue, autoradiography and immunolabeling have localized high density angiotensin (Ang) converting enzyme (ACE) and Ang II receptor binding to these cells, suggesting that they may regulate local concentrations of Ang II and transduce signals at this site. Ang II is known to modulate type I collagen gene expression of fibroblasts and myoFb, and to promote fibrous tissue contraction, each of which may contribute to tissue repair. It is unknown whether myoFb themselves generate Ang peptides de novo via expression of angiotensinogen (Ao), an aspartyl protease needed to convert Ao to Ang I, and ACE. We therefore isolated and cultured myoFb from 4-week-old scar tissue of the adult rat left ventricle with transmural MI. In cultured myoFb we found: (a) immunoreactive membrane-bound ACE, cytosolic cathepsin D (Cat-D), and AT, receptors by immunofluorescence and confocal microscopy, (b) mRNA expression for Ao, ACE, and Cat-D, but not renin, by reverse transcriptase-polymerase chain reaction, (c) production of Ang I and II in serum-free culture media; (d) absence of renin activity; (e) a time-dependent conversion of Ao to Ang I by myoFb cytosol, which was inhibited by pepstatin A, but not by renin inhibitor; and (f) significant increase in Ang II production (P < 0.05) by exogenous Ao and Ang I (10 nM), which was significantly blocked by lisinopril (0.1 microM: P < 0.05). Thus, cultured myoFb express requisite components and are able to generate Ang I and II de novo. In an autocrine and/or paracrine manner, Ang II may regulate myoFb collagen turnover and fibrous tissue contraction.
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PMID:Cultured myofibroblasts generate angiotensin peptides de novo. 920 23


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