Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests the involvement of a local renin-angiotensin system in some renal actions of angiotensin II (Ang II). In this study the renal distribution of the precursor to angiotensin formation, angiotensinogen, was investigated in rats and sheep using immunohistochemistry, immunoelectron microscopy and non-isotopic hybridization histochemistry. Immunostaining for angiotensinogen was seen in proximal tubules (PCT) of both rat and sheep kidneys. In the rat the strongest immunostaining was found in the kidneys of neonatal (1 day old) rats. Staining declined after birth. Non-isotopic hybridization histochemistry using oligodeoxynucleotide probes labeled with biotin confirmed the presence of angiotensinogen mRNA expression in PCT of the rat renal cortex. Electron microscopic immunohistochemistry using antibodies raised against rat angiotensinogen showed weak staining in the adult of granule-like structures close to the apical membrane of PCT cells. In the neonatal rat kidney, angiotensinogen immunostaining was found throughout the PCT cells and was markedly stronger than that seen in adult rat kidney. In sheep, angiotensinogen immunostaining with an antibody raised against purified ovine angiotensinogen showed staining of PCT in fetal, newborn and adult sheep kidney. The strongest immunostaining seen was in fetal sheep kidney with a decline seen after birth. Reverse transcription polymerase chain reaction (RT-PCR) showed that angiotensinogen mRNA was expressed in the sheep kidney at all ages studied. Angiotensinogen expression was higher in fetal sheep kidneys (77 day and 141 day gestation) than in adult sheep kidney. In conclusion, angiotensinogen mRNA expression was detected in both rat and sheep kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular and ultrastructural location of angiotensinogen in rat and sheep kidney. 770 5

This study focuses on the renin-angiotensin system (RAS) in the cerebellar cortex and changes within this system after mechanically induced cerebellar injury. Using radioactive and non-radioactive in situ hybridization and immunocytochemistry angiotensinogen mRNA, angiotensinogen, angiotensin II and, for the first time, N-terminal angiotensin fragment (1-7) immunoreactivities, respectively, were demonstrated in the rat cerebellum. Angiotensinogen mRNA and angiotensinogen immunoreactivity (IR) were both present in glial cell populations of all layers, especially in the Purkinje and granular cell layers and within the cerebellar nuclei. Angiotensin II IR was demonstrated in glial cell populations in all layers using a monoclonal angiotensin II antibody, while with a polyclonal angiotensin II antiserum (Denise) some Purkinje cell bodies were labelled. After lesioning the cerebellar cortex mechanically by an injection cannula a strong increase in angiotensinogen gene expression as well as in angiotensin II and angiotensin (1-7) immunoreactivities were observed in the glial cell populations. Furthermore, putative Bergmann glial processes, as indicated from the morphological appearance became strongly angiotensin II and angiotensinogen immunoreactive in the region close to the mechanically induced lesion. It could inter alia be demonstrated for the first time using confocal laser microscopy of ANG II IR and GFAP IR that ANG II in vivo in the intact cerebellar cortex is present in astroglial processes in the molecular layer and presumably secreted into the extracellular space in form of small spheric bodies and/or taken up by other cell types. In contrast, the N-terminal fragment angiotensin (1-7) IR was restricted to the glial cell populations and appeared only after the lesion event. Thus, it is suggested that the cerebellar RAS shows marked changes in response to mechanically induced lesions. The expression of angiotensinogen as well as the production of angiotensinogen IR and angiotensin II like IR is even after mechanical lesion restricted to astrocytes, i.e., cerebellar astrocytes and putative Bergmann glial cells, and in case of immunoreactivities it spreads to the radially oriented Bergmann glial processes in the molecular layer.
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PMID:On the plasticity of the cerebellar renin-angiotensin system: localization of components and effects of mechanical perturbation. 770

We hypothesized that the gene expression of angiotensinogen, angiotensin-converting enzyme, and angiotensin II type 1 receptor, in addition to renin, is increased in kidneys after renal artery stenosis. Two-kidney, one clip renovascular hypertension was initiated in Sprague-Dawley rats by clipping of the left renal artery; control rats were sham operated. Blood pressure was not changed for the first 2 days after clipping but was elevated on day 4 (mean arterial pressure, 104 +/- 4 versus 87 +/- 2 mm Hg in sham-operated control rats, P < .002) and increased further during the next 24 days. Rats were killed 2, 4, 7, 14, and 28 days after clipping or sham operation, and poly(A)(+)-purified renal cortical RNA was analyzed by Northern blotting. Autoradiographs were quantitated by densitometry and normalized for the expression of a housekeeping gene. Renin expression was increased in the clipped kidney (by 149% on day 2) and decreased in the nonclipped kidney (by 82% on day 2), compared with kidneys of control rats. Expression of the angiotensin-converting enzyme was increased in clipped kidneys from the first day after clipping (158%) and throughout the experiment (66% on day 28), but was unchanged or slightly decreased in nonclipped kidneys. Angiotensinogen mRNA showed little change. Angiotensin II type 1 receptor expression was decreased in nonclipped kidneys but unchanged during the first 7 days in clipped kidneys. Our results show that components of the renin-angiotensin system other than renin are also differentially expressed in clipped kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of angiotensin-converting enzyme in renovascular hypertensive rat kidney. 772 14

The components of the Renin-Angiotensin System (RAS) have been found to be expressed in the brain. Angiotensinogen, the high molecular weight precursor of the system, is widely distributed and expressed in areas not related to control of blood pressure and body fluid homeostasis as well. It has been shown that it is regulated by steroid hormones independently from the liver and that it is also regulated in a different manner in several brain areas. Angiotensin II, the effector peptide of the system, may be generated in the brain via the classical pathway, using renin and angiotensin converting enzyme or directly from angiotensinogen by cathepsin G or tonin. N-terminal peptides of angiotensin II have been found in several brain areas with ANG (1-7) involved in vasopressin release however without influence on blood pressure and with ANG III acting as potent as ANG II. Transgenic animals may be used to study the pathophysiology of an activated brain RAS.
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PMID:The brain renin-angiotensin system: molecular mechanisms of cell to cell interactions. 773 73

Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues. In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in Km (from 1.1 to 0.09 microM) and a 5-fold decrease in kcat (from 1.0 to 0.22 s-1); as a result, catalytic efficiency (kcat/Km) is increased by a factor of 2 (1.1 versus 2.4 microM-1 s-1). In the reaction of angiotensin-converting enzyme on angiotensin decapeptides, the substitution has no effect on Km (38.0 versus 30.0 microM), but increases kcat and catalytic efficiency > 2-fold (kcat = 15.0 versus 37.0 s-1; kcat/Km = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.
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PMID:A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. 774 80

Several genes, including some encoding components of the renin angiotensin system, are associated with the risk of cardiovascular diseases. There have been reports linking a homozygous deletion allele of the angiotensin converting enzyme (ACE) gene (DD) with an increased risk of myocardial infarction, and some variants of the angiotensinogen gene with an increased risk of hypertension. In a case-control study of a caucasian population from New Zealand, we examined the associations with coronary heart disease (CHD) of ACE DD and of a mis-sense mutation with methionine to threonine aminoacid substitution at codon 235 in the angiotensinogen gene (T235). We studied 422 patients (mean age 62 years, 81% male) with documented CHD (50% with myocardial infarction) and 406 controls without known CHD (frequency-matched to cases by age and sex). Risk factors for CHD were assessed by standard questionnaire, physical examination, and blood tests. Genomic DNA from leucocytes was analysed for various ACE and angiotensinogen alleles. Angiotensinogen T235 homozygotes were at significantly increased risk of CHD generally (odds ratio 1.7, 2 p = 0.008) and of myocardial infarction specifically (1.8, 2 p = 0.009). Adjustment for several risk factors increased the estimate of CHD risk associated with this allele to 2.6 (2 p < 0.001) and the estimate for myocardial infarction risk to 3.4 (2 p < 0.001). By contrast, there was no evidence of a significant increase in the risk of CHD or myocardial infarction among individuals with ACE DD. We conclude that the T235 polymorphism of the angiotensinogen gene is an independent risk factor, which carries an approximately two-fold increased risk of CHD. In this study, however, ACE DD was not associated with any detectable increase in CHD risk.
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PMID:Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. 763 19

This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163 +/- 12 to 110 +/- 9 mm Hg, P < .05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 +/- 6 to 96 +/- 6mm Hg, P < .05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156 +/- 9 to 132 +/- 5 mm Hg, P < .05) than in sham (104 +/- 3 to 94 +/- 4 mm Hg, P < .05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8 +/- 8.3 versus 95.7 +/- 10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42 +/- 1.58 versus 6.74 +/- 2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4 +/- 3.0 versus 26.0 +/- 2.4 ng Ang I/mL, P < .05) and in the artery wall of hypertensive conscious rats (103.1 +/- 10.3 versus 75.2 +/- 7.8 ng Ang I/g, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of EXP 3174 on blood pressure of normoreninemic renal hypertensive rats. 784 80

The renin-angiotensin system (RAS) functions as a primary regulator in the short-term and long-term control of blood pressure. Pharmacologic inhibition of the RAS with angiotensin-converting enzyme (ACE) inhibition is effective for treating systemic hypertension and congestive heart failure. As a more specific therapy, the development of renin inhibitors has evolved through various approaches: specific renin antibodies, peptides developed from prosegments of renin precursor, oligopeptides related to pepstatin a universal inhibitor of aspartyl proteinase enzyme, and analogs of angiotensinogen (the renin substrate). Angiotensinogen analogs are promising as therapeutic agents because of high potency, metabolic stability, and good oral bioavailability. Ongoing research is directed towards the application of renin inhibition, the treatment of various cardiovascular disorders, and as a biological probe for understanding the role of the RAS in control of blood pressure and blood volume.
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PMID:Renin inhibition: a new approach to cardiovascular therapy. 798 30

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma.
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PMID:Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis. 799 42

It has been hypothesized that the renin-angiotensin system plays a pathophysiologic role in the renal hemodynamic abnormalities that occur in diabetes mellitus and thereby contributes to the development of diabetic nephropathy. In this study, the tissue-specific regulation of renin and angiotensinogen mRNA levels and the abundance of glomerular angiotensin II receptors were examined in male Sprague-Dawley rats (160 to 240 g) made diabetic with streptozotocin. One subgroup of diabetic rats remained untreated, whereas a second diabetic subgroup received twice-daily doses of insulin to ameliorate hyperglycemia. Animals were euthanized 2 wk after the induction of diabetes. Mean plasma glucose levels at the time of euthanasia were significantly elevated in the untreated diabetic animals when compared with controls or insulin-treated diabetic rats. Weight gain was similar in control and insulin-treated diabetic rats, whereas the untreated diabetic rats gained significantly less. Plasma renin concentration did not differ between control, diabetic, and insulin-treated diabetic groups. In the kidney, no significant differences were found in either angiotensinogen or renin mRNA levels in diabetic animals, whereas glomerular angiotensin II receptors were significantly less abundant in untreated rats as compared with control or insulin-treated diabetic subgroups. Angiotensinogen mRNA levels were significantly lower in the livers and adrenals of diabetic rats in comparison to those in controls and insulin-treated diabetic rats, whereas angiotensinogen mRNA levels in the brain remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat. 813 Mar 60


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