angiotensinogen and Hypertension--Malignant

Topics: Adrenergic beta-Antagonists; Adult; Aldosterone; Angiotensinogen; Angiotensins; Animals; Blood Pressure; Female; Humans; Hyperaldosteronism; Hypertension; Hypertension, Malignant; Hypertension, Renovascular; Kidney Failure, Chronic; Male; Molecular Weight; Peptidyl-Dipeptidase A; Radioimmunoassay; Renin

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats (n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Cytochrome P-450 CYP1A1; Gene Expression; Hypertension, Malignant; Indoles; Kidney Cortex; Kidney Medulla; Kidney Tubules, Collecting; Male; Prorenin Receptor; Rats; Rats, Transgenic; Receptors, Cell Surface; Renin; Renin-Angiotensin System

Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension.. This study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n = 6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension.. Rats induced with I3C exhibited pronounced increases in systolic blood pressure (208 ± 7 versus 127 ± 3 mm Hg; P < 0.001), marked proteinuria (29.4 ± 3.6 versus 5.9 ± 0.3 mg/d; P < 0.001) and augmented urinary angiotensinogen excretion (996 ± 186 versus 241 ± 31 ng/d; P < 0.01). Chronic administration of the AT₁ receptor antagonist, candesartan (25 mg/L in drinking water, n = 6), prevented the I3C-induced increases in systolic blood pressure (125 ± 5 mm Hg; P < 0.001), proteinuria (7.3 ± 1.0 mg/d; P < 0.001) and urinary angiotensinogen excretion (488 ± 51 ng/d, P < 0.01).. These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Cytochrome P-450 CYP1A1; Humans; Hypertension, Malignant; Male; Middle Aged; Rats; Rats, Transgenic; Renin; Tetrazoles

Topics: Angiotensinogen; Humans; Hypertension, Malignant; Polymorphism, Genetic; Promoter Regions, Genetic

Malignant hypertension can be considered an extreme phenotype of renin-mediated hypertension. Therefore, we compared the allelic frequencies of the angiotensinogen (AGT) M235T, angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II-type I receptor (AT1R) A1166C polymorphisms in malignant hypertensive patients with hypertensive and normotensive controls.. A total of 101 consecutive patients between 1995 and 2005 admitted to a large university hospital fulfilled the criteria for malignant hypertension. Seventy-five patients (74%) were compared with 150 hypertensive and 150 normotensive controls, randomly selected from a population study and individually matched on age, sex and ethnicity.. The odds of malignant hypertension in white subjects with the TT genotype of the AGT M235T polymorphism was 14.3 (5.5-37) compared to hypertensive controls, and 9.4 (3.8-23.2) compared to normotensive controls. Adjustment for age, sex, smoking and antihypertensive therapy did not affect this association. The association of AGT M235T with malignant hypertension was not significant in blacks. In patients with malignant hypertension, the TT genotype was associated with more severe renal dysfunction and microangiopathic haemolysis. No differences were found in allele frequencies of the ACE I/D or the AT1R A1166C polymorphisms between study groups.. The TT genotype of AGT M235T is associated with malignant hypertension in whites, carriers having an odds of approximately 10 to 1 compared to hypertensive and normotensive controls. These observations may provide a better understanding of the pathophysiology of malignant hypertension and offer possibilities for identifying patients at risk. Larger association or linkage studies are needed for a more detailed risk assessment.

Topics: Adult; Aged; Angiotensinogen; Female; Gene Frequency; Genotype; Humans; Hypertension, Malignant; Male; Middle Aged; Polymorphism, Genetic; Risk

We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither transgenic strain was hypertensive. These strains were then crossed, producing a double transgenic strain. The double transgenic rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269 +/- 381 (+/-SD) ng angiotensin I (Ang I)/mL per hour, plasma renin activity of 177 +/- 176 ng Ang I/mL per hour, rat angiotensinogen concentration of 1.49 +/- 1 microgram Ang I/mL, and human angiotensinogen concentration of 78 +/- 39 micrograms Ang I/mL (n = 49). Control rats had plasma renin activity of 3.7 +/- 3.9 ng Ang I/mL per hour and rat angiotensinogen of 1.32 +/- 0.16 micrograms Ang I/mL. Angiotensinogen transgene expression by RNase protection assay was ubiquitously present but most prominent in liver. Renin transgene expression was high in kidney but absent in liver. The rats featured severe cardiac hypertrophy, with increased cross section of cardiomyocytes but little myocardial fibrosis. The kidneys showed atrophic tubules, thickened vessel walls, and increased interstitium. Both the angiotensin-converting enzyme inhibitor lisinopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gene expressions are similar. The specificity of rodent and human renin is similarly documented. Although many elegant physiological studies can now be done in mice, rats nevertheless offer flexibility, particularly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simultaneous investigation of genetic and pathophysiological aspects of renin-induced hypertension. The fact that human renin can be studied in the rat is a unique feature of this model.

Topics: Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiomegaly; Crosses, Genetic; Disease Models, Animal; Female; Humans; Hypertension, Malignant; Kidney; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renin

Topics: Angiotensinogen; Angiotensins; Animals; Brain Chemistry; Hematocrit; Hypertension, Malignant; Hypertension, Renal; Hypothalamus; Male; Rats; Rats, Inbred Strains; Renin

The objective of this investigation was to determine whether heterogeneity of plasma renin substrate could be observed in states of steroid excess and various forms of hypertensive disease. In states of stimulated renin substrate production by estrogens or glucocorticoids, multiple forms of renin substrate were apparent when stimulation was excessive. Stimulation of substrate production caused by uremia associated with hypertension showed similar results. None, or only trace quantities of the additional forms of renin substrate were evident in subjects with normal or suppressed levels of plasma renin substrate. The additional forms of renin substrate could be distinguished from the normal form on the basis of cross-reactivity with a specific antiserum to the normal form, electrophoretic mobility, and kinetic rate constants. Differences in rate constants of the various forms of plasma renin substrate may account for the altered rate of the renin reaction associated with several states of hypertension. In plasma of patients with renovascular hypertension, significant quantities of a protein which cross-reacted with the antiserum but could not generate angiotensin I were observed.

Topics: Angiotensinogen; Angiotensins; Contraceptives, Oral; Cushing Syndrome; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Pregnancy; Uremia

The relationship between plasma renin activity (PRA), angiotensin II (AT II) and renin substrate concentration (PRS) were studied in a patient with left renal artery occlusion and malignant hypertension before and after left-side nephrectomy. Initially, PRA and AT II were grossly elevated, while PRS was low. Treatment with alpha-methyl-DOPA and saline led to a fall in PRA and AT II and a large rise in PRS. The correlation between PRA and AT II (r=0.937; n=9, p less than 0.001) was highly significant. PRA and PRS were negatively correlated before operation (r=-0.78; n=6; p less than 0.05). A comparison of changes in PRS before and after nephrectomy suggests that renin substrate formation was increased when the ischemic kidney was still in situ. Following nephrectomy, PRA and blood pressure fell to normal within 5 hours, while PRS remained unchanged for this period of time. A two-compartmental analysis of the renin disappearance curve after nephrectomy revealed the presence of a fast and slow component with half-lives of 10 and 95 min, respectively.

Topics: Angiotensin II; Angiotensinogen; Humans; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Nephrectomy; Renal Artery Obstruction; Renin