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A Fogo

Publications and source records attributed to A Fogo.

At least 19 recordsLinked to original sources
PubMed1997

Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion.

Wild-type (Agt+/+) and homozygous angiotensinogen deletion mutant (Agt-/-) littermates were placed on normal (NS) or low Na diet (LS) for 2 weeks. Plasma aldosterone levels (P(aldo)) were comparable during NS, and similarly elevated during LS in Agt+/+ and Agt-/-. Moreover, in both, the elevation in P(aldo) was accompanied by marked increase in adrenal zona glomerulosa cells and adrenal P450aldo mRNA. Agt-/- mice were distinguished from Agt+/+ mice by their higher plasma K level, by approximately 1.5 and approximately 3.8 mEq/liter during NS and LS, respectively. Within the Agt-/- group, P(aldo) was directly proportional to plasma K. The importance of K for the hyperaldosteronism during dietary Na restriction was verified by the observation that superimposition of K restriction led to hypotension in Agt+/+ and uniform death in Agt-/- mice along with a reduction in P(aldo) by 75 and 90%, respectively. Thus, suppression of potassium, but not angiotensin, led to a marked attenuation of hyperaldosteronism during dietary Na restriction. Therefore, (a) a powerful angiotensin-independent mechanism exists for the hyperaldosteronism during LS; (b) high K is a central component of this mechanism; (c) contrary to current belief, the tonic effect of high K on aldosterone synthesis and release does not require an intact renin-angiotensin system; and (d) normally, intermediary feedback signals for hyperaldosteronism, i.e., both hypotension and high K, are effectively masked by aldosterone actions.

Adrenal Glands↗
PubMed1997

A 51-year-old woman with nephrotic syndrome, hematuria, and renal insufficiency.

This case illustrates the utility of all modalities of the renal biopsy in arriving at a correct diagnosis in an adult patient with nephrotic syndrome. Unlike the clinical situation in children, where minimal change disease is presumed to underlie the nephrotic syndrome unless the patient shows steroid resistance, the list of differential diagnosis of nephrotic syndrome in the adult is lengthy. The renal biopsy is essential in establishing the specific diagnosis. We discuss the diagnostic approach in an adult patient with a relatively uncommon disease causing the common manifestations of nephrotic syndrome, hematuria and renal insufficiency.

Biopsy↗
PubMed1997

Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition.

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Angiotensin II↗
PubMed1997

Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK Pilot Study Investigators.

African Americans have excess hypertension and end-stage renal disease presumed due to hypertension compared to Caucasians. The AASK was designed to examine the impact of antihypertensive therapies and two levels of blood pressure control on the rate of decline of GFR in African Americans with presumed hypertensive renal disease. During the pilot phase of the trial, eligible participants were requested to undergo renal biopsy to assess the underlying lesions in this population. Eighty-eight hypertensive (diastolic BP > 95 mm Hg) non-diabetic African American patients between the ages of 18 to 70 years, with GFR between 25 to 70 ml/min/1.73 m2 and without marked proteinuria were assessed for possible renal biopsy. Forty-three patients did not undergo renal biopsy due to refusal or contraindications. Adequate renal biopsies were obtained in 39 of the remaining 46 patients. Biopsy findings were analyzed and then compared to clinical parameters. The 39 patients studied, 29 men and 10 women, were on average 53.0 +/- 11.0 years old, and had a MAP of 109 +/- 15 mm Hg and GFR 51.7 +/- 13.6 ml/min/1.73 m2 (not significantly different from nonbiopsied patients). Thirty-eight of these 39 biopsies showed arteriosclerosis and/or arteriolosclerosis, severity on average 1.5 +/- 0.9 and 1.5 +/- 0.8, respectively on a 0 to 3+ scale. Interstitial fibrosis was moderate, 1.3 +/- 0.9 (0 to 3+ scale). Segmental glomerulosclerosis was present in five biopsies, and in one patient, biopsy and clinical findings were consistent with idiopathic focal segmental glomerulosclerosis. Additional lesions included mesangiopathic glomerulonephritis in one patient, basement membrane thickening suggestive of diabetic nephropathy in one, and cholesterol emboli in two cases. Arteriolar and arterial sclerosis were tightly linked, and correlated with interstitial fibrosis and the reciprocal of serum creatinine. Global glomerulosclerosis was extensive, involving on average 43 +/- 26% of glomeruli. The extent of this lesion did not correlate with degree of arteriolar or arterial thickening, but did correlate with systolic blood pressure (P = 0.0174), the reciprocal of serum creatinine (P = 0.0009), serum cholesterol (P = 0.0129) and interstitial fibrosis (P < 0.0001). These data underscore that renal biopsies in non-diabetic hypertensive African-Americans with mild to moderate renal insufficiency in the absence of marked proteinuria are overwhelmingly likely to show renal vascular lesions consistent with the clinical diagnosis of hypertensive nephrosclerosis.

Adult↗
PubMed1997

A novel in vivo mechanism for angiotensin type 1 receptor regulation.

This study examined whether a regulatory mechanism exists for the angiotensin II receptor that is compatible with in vivo homeostatic need. Experiments were conducted under two different experimental stresses, (1) deletion of receptor protein and (2) chronic extracellular fluid (ECF) volume depletion. To circumvent potentially dampening intermediary feedback signals in vivo, any feedback gain was completely averted through genetic engineering. The coding exon of angiotensin type 1A (AT1A) receptor gene (Agtr1a) was targeting-replaced with a reporter gene, lacZ, so that the transcription of lacZ, instead of Agtr1a, is driven by the native Agtr1a promoter. ECF volume depletion by dietary sodium restriction enhanced Agtr1a gene expression in the adrenal gland of wild-type mice. However, although blood pressure fell in the homozygous targeted mice, Agtr1a gene expression remained unchanged in the adrenal, indicating that adrenal Agtr1a gene expression is regulated entirely through angiotensin receptor-ligand interactions. In the kidney, AT1A mRNA assessed by Northern blotting also did not change in AT1A null-mutated mice with or without sodium restriction. However, tissue examinations for lacZ mRNA and activities indicated that sodium restriction and receptor protein depletion result in dramatic up-regulation of Agtr1a gene expression within the renal arterioles, which can be nullified by an experimental normalization of blood pressure. No such change was observed in wild-type mice. This study demonstrates a presence within the resistance vessel of a blood pressure-sensitive mechanism for AT1 receptor regulation that opposes a down-regulatory influence of the ligand during ECF volume depletion.

Adrenal Glands↗
PubMed1997

Temporal and spatial expression pattern of the angiotensinogen gene in mice and rats.

In situ hybridization for mouse angiotensinogen (Ao) mRNA was performed using a Stu I-Pst I 0.43-kb fragment of exon 2 as a template to synthesize RNA probes. The mouse Ao mRNA expression patterns were different from those reported for rats. Ao mRNA was expressed in the fetal liver as early as 12.5 days postcoitus, and the liver remained the predominant organ of its expression in utero. Within the developing kidney, Ao mRNA was demonstrated at 17.5 days postcoitus in the proximal straight tubules undergoing loop formation in the medulla. In the matured mouse kidney, the expression site is within the outer stripe of outer medulla, hence identified as the pars recta, not proximal convoluted tubules. Additional studies revealed that, in rats also, Ao mRNA was localized in the pars recta. This was in contrast to previously published results that showed that Ao mRNA was localized primarily in the proximal convoluted tubules in rats. Thus the pars recta appears to be an important intrarenal source of Ao for both rats and mice throughout pre- and postnatal periods, whereas the liver can be the major extrarenal source in utero in mice, but not in rats.

Aging↗
PubMed1997

Targeting deletion of angiotensin type 1B receptor gene in the mouse.

We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

Aldosterone↗
PubMed1997

Targeting the genes of angiotensin receptors.

Gene targeting technology has produced mutant mice carrying selective null-mutation of the genes for the components of the renin-angiotensin system. Angiotensinogen null-mutant mice showed not only severe hypotension, but also several abnormal phenotypes in the kidney, including juxtaglomerular (JG) cell hypertrophy, renal arterial hypertrophy, and hypoplastic papilla. Although angiotensin type 1A (AT1A) receptor is by far the most predominant in mice, the phenotypes of AT1A null-deletion mice are much milder than those of angiotensinogen null-mutant mice. Because renin and angiotensin (ANG) production is upregulated in AT1A null-mutant mice, it is conceivable that the AT1B receptor provides compensation for the lost functions of AT1A. The observations in mice with complete absence of a gene product have not elucidated whether the abnormal phenotypes reflect direct effects caused by lack of local tissue action of ANG II or a secondary effect caused by changes in systemic milieu. We have developed chimeric mice that are made up of a mix of clusters of wild-type cells: cells homozygous for AT1A gene deletion. Within a given chimeric mouse, the expressions of renin mRNA and protein are identical between wild-type and mutant cells. In addition, all of the chimeric mice lack the renal arterial lesion observed in standard AT1A null-mutant mice. These findings indicate that both JG cell hypertrophy and renal vascular lesions are caused by systemic, rather than local, mechanism(s).

Angiotensin II↗
PubMed1996

Chimeric mice carrying 'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells.

We have developed chimeric mice carrying 'regional' null mutation of the angiotensin type 1A (AT1A) receptor, the AT1 receptor subtype exclusively present in mouse juxtaglomerular (JG) cells. The chimeric mouse (Agtr1a -/- <--> +/+) is made up of wild-type (Agtr1a +/+) cells or cells homozygous for Agtr1a deletion (Agtr1a -/-). In the latter, the AT1A coding exon was replaced with a reporter gene, lacZ. In Agtr1a -/- <--> +/+ mice, these two clones of cells are found to be clustered and display patchy distributions in the kidney and heart. Tracking of lacZ activities in hetero- (Agtr1a +/-) and homozygous (Agtr1a -/-) deletion mutant offspring from Agtr1a -/- <--> +/+ mice revealed that the promoter activity of Agtr1a is localized in JG cells, afferent arteriolar walls, glomerular mesangial region and endothelial cells, and apical and basolateral proximal tubule membranes. The JG apparatuses of Agtr1a -/- mice are markedly enlarged with intense expression of renin mRNA and protein. In Agtr1a -/- <--> +/+ mice, these changes were proportional to the degree of chimerism. Within a given Agtr1a -/- <--> +/+ mouse, however, the degree of JG hypertrophy/hyperplasia and the expression of renin mRNA and protein were identical between Agtr1a +/+ and Agtr1a -/- cells. Thus, in the in vivo condition tested, the local interaction between angiotensin and the AT1 receptor on the JG cells has little functional contribution to the feedback regulation of JG renin synthesis.

Angiotensins↗
PubMed1996

Focal segmental glomerulosclerosis.

Over the last 2 decades, we have learnt that focal segmental glomerulosclerosis (FSGS) is a ubiquitous phenomenon underlying the progressive deterioration of many different types of renal diseases in both pediatric and adult populations. FSGS may also be the primary renal lesion, whether in new disease entities such as glycogen storage disease and human immunodeficiency virus infection, or in idiopathic FSGS. Although the mechanism which triggers the development of primary FSGS still remains unknown, laboratory and clinical studies have identified several key pathophysiological events leading to end-stage renal disease. While therapeutic modalities have not changed remarkably, a recent study, although uncontrolled, demonstrated an impressive efficacy of intravenous steroid pulse therapy in inducing remission. Nevertheless, it remains largely unknown whether such a forced remission decreases the overall risk of developing chronic renal failure. Studies have revealed an important pathophysiological role of angiotensin and the therapeutic efficacy of angiotensin converting enzyme inhibitors in progressive loss of renal function in diseases where glomerulosclerosis is secondary; however, it remains to be verified whether these results hold true in primary FSGS. As a result of the improvement in allograft survival rate, the benefit of renal transplant outweighs the risk of recurrence of FSGS, hence transplantation continues to be a vital therapy for FSGS patients who have reached renal failure. Thus, FSGS is not one disease, but rather a range of lesions seen in many settings. The type of lesions and the patient's unique genetic factors contribute to prognosis, and also may dictate choice of optimum therapy.

Animals↗
PubMed1996

Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy.

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.

Alleles↗
PubMed1996

Treatment of hypertension.

Effectiveness of antihypertensive agents is assessed not only by systemic blood pressure levels, but by multiple parameters that reflect specific organ functions. Among antihypertensive agents, those which inhibit angiotensin actions show particular efficacy in ameliorating end organ damage. This efficacy likely reflects the central role that angiotensin has in regulating renal function by its multifaceted actions. We will therefore focus on the renin angiotensin system, and compare its actions on parameters of renal injury with other antihypertensive treatment approaches.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Angiotensin II↗
PubMed1995

Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Studies in chronic cyclosporine nephrotoxicity in rats.

Both functional and structural damage characterize nephrotoxicity due to cyclosporine (CsA) with accumulating evidence for dissociation of mechanisms that lead to each of these processes. We studied the role of endothelin (Et) and angiotensin II (AII), since each of these peptides can modulate vasoconstriction as well as parenchymal destruction. Salt-depleted rats were treated with daily CsA (15 mg/kg s.c.) for 5 weeks (group 1, CsA, n = 13). Separate groups of CsA-treated rats received either a combined antagonist of both EtA/EtB receptors (group 2, CsA+aEtA/B, 100 mg/kg/day p.o., n = 6) or angiotensin I-converting enzyme inhibitor (group 3, CsA+ACEI, enalapril 200 mg/L drinking water, n = 8). Glomerular filtration rate (GFR) was assessed by creatinine clearance (Ccr) in conscious rats at 3 and 5 weeks. At 3 weeks, serum creatinine was 1.5 +/- 0.1 mg/dl in group 1 rats, 1.2 +/- 0.2 mg/dl in group 2 rats (P < 0.05 vs. CsA), and 2.3 +/- 0.8 mg/dl in group 3 rats. Ccr was 0.87 +/- 0.08 ml/min in group 1. In group 2, GFR was remarkably preserved (1.14 +/- 0.11 ml/min, P < 0.05 vs. group 1). By contrast, GFR in group 3 rats was lower (0.31 +/- 0.08 ml/min) than either aEtA/B-treated or even CsA-treated rats (P < 0.0005 vs. group 1, P < 0.0005 vs. group 2). At 5 weeks, the same pattern emerged; serum creatinine was 2.5 +/- 0.2 mg/dl in group 1, 1.2 +/- 0.1 in group 2 (P < 0.0005 vs. CsA), and 3.4 +/- 0.9 in group 3 (P < 0.025 vs. CsA+aEtA/B). Ccr had decreased dramatically in CsA-treated rats to 0.18 +/- 0.03 ml/min. GFR was preserved in CsA+aEtA/B rats (0.51 +/- 0.03 ml/min, P < 0.0005 vs. group 1), while profound hypofiltration was apparent in CsA+ACEI rats (0.12 +/- 0.03 ml/min, P < 0.0005 vs. group 2). In salt-depleted control animals, GFR was 0.62 +/- 0.02 ml/min. Despite striking functional preservation in response to antagonism of Et receptors, tubular vacuolization/dilatation, as well as arteriolopathy, was not different among the CsA-treated groups. Tubulointerstitial fibrosis was also not different between CsA and CsA+aEtA/B rats (on a 0-4 scale, 1.05 +/- 0.14 vs. 0.87 +/- 0.14, P = NS). In contrast, both tubular vacuolization/dilatation and interstitial fibrosis were significantly greater in all CsA-treated groups compared with salt-depleted controls. However, in the CsA+ACEI group that had the most severe hypofiltration at each time point, tubulointerstitial fibrosis was 0.69 +/- 0.06 (P < 0.05 vs. CsA).(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗