PubMed Health⌕ Search

Biomedical subjects

R Ariel Gomez

Publications and source records attributed to R Ariel Gomez.

14 recordsLinked to original sources
PubMed2006

Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption.

We have determined that differences in expression of aldosterone synthase (AS) affect responses to a low-salt diet. In AS-null mice (AS(-/-)), but not in wild-type, low salt significantly decreased plasma sodium and increased potassium. The increased urine volume (1.5xwild-type) and decreased urine osmolality (0.7xwild-type), present in AS(-/-) mice on normal salt, became more severe (2.3xwild-type and 0.5xwild-type) on low salt, but neither changed in wild-type. In both genotypes, plasma vasopressin was similar on normal and low salt, and desmopressin injection significantly increased urine osmolality. Renal mRNA levels for aquaporin 1 and 3 were unchanged by genotype or diet and epithelial sodium channel and Na(+)-K(+)-2Cl(-)-cotransporter by genotype. In AS(-/-) mice, aquaporin 2 mRNA increased on normal salt, whereas Na(+)Cl(-)-cotransporter and cortex K(+) channel mRNAs decreased on both diets. The low blood pressure of AS(-/-) mice was decreased further by low salt, despite additional increases in renin, intrarenal arterial wall thickness, and macula densa cyclogenase-2 mRNA. In AS(+/-) mice on normal salt, adrenal AS mRNA was slightly decreased (0.7xwild-type), but blood pressure was normal. On low salt, their blood pressure was less than wild-type (101+/-2 mm Hg versus 106+/-2 mm Hg), even though renin mRNA increased to 2xwild-type. We conclude that aldosterone is critical for urine concentration and maintenance of blood pressure and even a mild reduction of AS expression makes blood pressure sensitive to low salt, suggesting that genetic differences of AS levels in humans may influence how blood pressure responds to dietary salt.

Adrenal Glands↗
PubMed2006

Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells.

By crossing mice with expression of Cre recombinase under control of the endogenous renin promoter (Sequeira Lopez ML, Pentz ES, Nomasa T, Smithies O, Gomez RA. Dev Cell 6: 719-728, 2004) with mice in which exon 1 of the Gnas gene was flanked by loxP sites (Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, Nackers LM, Lorenzo J, Shen L, Weinstein LS. Proc Natl Acad Sci USA), we generated animals with preferential and nearly complete excision of Gsalpha in juxtaglomerular granular (JG) cells. Compared with wild-type animals, mice with conditional Gsalpha deficiency had markedly reduced basal levels of renin expression and very low plasma renin concentrations. Furthermore, the acute release responses to furosemide, hydralazine, and isoproterenol were virtually abolished. Consistent with a state of primary renin depletion, Gsalpha-deficient mice had reduced arterial blood pressure, reduced levels of aldosterone, and a low glomerular filtration rate. Renin content and renin secretion of JG cells in primary culture were drastically reduced, and the stimulatory response to the addition of PGE(2) or isoproterenol was eliminated. Unexpectedly, Gsalpha recombination was also observed in the renal medulla, and this was associated with a vasopressin-resistant concentrating defect. Our study shows that Cre recombinase under control of the renin promoter can be used for the excision of floxed targets from JG cells. We conclude that Gsalpha-mediated signal transduction is essential and nonredundant in the control of renin synthesis and release.

Adrenergic beta-Agonists↗
PubMed2005

Kidney function in mice lacking aldosterone.

To explore the effects of decreased amounts or absence of aldosterone, we have disrupted the gene coding for aldosterone synthase (AS) in mice and investigated blood pressure and kidney function in AS+/+, AS+/-, and AS-/- mice. AS+/- mice have normal blood pressures and show no abnormalities in electrolytes or kidney gene expression, but they have significantly higher than normal urine volume and lower urine osmolality. In contrast, the AS-/- mice have low blood pressure, abnormal electrolyte homeostasis (increased plasma concentrations of K+, Ca2+, and Mg2+ and decreased concentrations of HCO3(-) and Cl- but no difference in the plasma Na+ level), and disturbances in water metabolism (higher urine output, decreased urine osmolality, and impaired urine concentrating and diluting ability). Absence of aldosterone in the AS-/- mice induced several compensatory changes: an increased food intake-to-body weight ratio, an elevated plasma concentration of glucocorticoids, and strong activation of the renin-angiotensin system. Parallel with the markedly increased synthesis and release of renin, the AS-/- mice showed increased expression of cyclooxygenase-2 (COX-2) in macula densa. On salt supplementation, plasma electrolyte concentrations and kidney renin and COX-2 levels became similar to those of wild-type mice, but the lower blood pressure of the AS-/- mice was not corrected. Thus absence of aldosterone in AS-/- mice results in impairment of Na+ reabsorption in the distal nephron, decreased blood pressure, and strong renin-angiotensin system activation. Our data show the substantial correction of these abnormalities, except the low blood pressure, by high dietary salt does not depend on aldosterone.

Acid-Base Equilibrium↗
PubMed2005

Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice.

To study the effects of decreased amounts or absence of aldosterone on development and endocrine function, we have disrupted the mouse gene, Cyp11b2, coding for aldosterone synthase (AS) by replacing its first two exons with sequences coding for enhanced green fluorescent protein. The null pups fail to thrive postnatally, and about 30% die between d 7 and 28. Aldosterone in plasma and AS mRNA in adrenal glands are undetectable in the null mice. Adult AS-null mice are small, weigh 75% of wild type, are hypotensive, have increased concentrations of plasma K(+) and corticosterone, and a decreased concentration of plasma Cl(-). Their plasma renin and angiotensin II concentrations are 45x and 4x wild type. The adrenal cortex is disorganized and has cells that contain marked accumulations of lipid. The zona glomerulosa is widened and includes easily detectable renin-containing cells, not seen in the wild-type adrenal gland. In the AS-/- adrenals, the level of mRNA for Cyp11b1, coding for 11beta-hydroxylase, is 150% wild type. The adrenal glands of the null mice consequently show evidence of a greatly activated renin-angiotensin system and up-regulation of glucocorticoid production. In the AS-null mice enhanced green fluorescent protein fluorescence is mainly at the boundary between the cortex and medulla, where apoptotic cells are numerous. These data are consistent with the absence of aldosterone in the AS-null mice inducing an increased cell-turnover of cells in the adrenals that normally become AS expressing and their migration to the medullary boundary where they apoptose.

Adrenal Cortex↗
PubMed2004

Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type.

Mice lacking Ren1c were generated using C57BL/6-derived embryonic stem cells. Mice homozygous for Ren1c disruption (Ren1c-/-) are born at the expected ratio, but approximately 80% die of dehydration within a few days. The surviving Ren1c-/- mice have no renin mRNA expression in the kidney, hydronephrosis, thickening of renal arterial walls, and fibrosis in the kidney. Plasma renin and angiotensins I and II are undetectable. Urinary aldosterone is 6% wild-type. They have low tail-cuff BP (84 +/- 4 versus 116 +/- 5 mmHg in +/+) and excrete large amounts of urine (5.2 +/- 0.8 ml/d, 725 +/- 34 mOsm versus 1.1 +/- 0.1 ml/d, 2460 +/- 170 mOsm in +/+). After 5 d of drinking 5% dextrose, desmopressin does not increase the osmolality of the urine in -/- mice (624 +/- 19 to 656 +/- 25 mOsm), whereas in +/+, it increases severalfold (583 +/- 44 to 2630 +/- 174 mOsm). Minipump infusion of angiotensin II to Ren1c-/- mice restores BP to wild-type level, but preexisting damage to the medulla prevents complete restoration of the ability of the kidney to concentrate urine. Heterozygous Ren1c+/- mice, in contrast, are indistinguishable from +/+ in BP, urine volume, and osmolality. Kidney renin mRNA, the number of kidney cells producing renin, and plasma renin concentration in the Ren1c+/- mice are also indistinguishable from +/+. These results demonstrate that renin is the only enzyme capable of maintaining plasma angiotensins and that renin expression in the kidney is very tightly regulated at the mRNA level.

Angiotensin II↗
PubMed2004

Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened.

Renin-synthesizing cells are crucial in the regulation of blood pressure and fluid-electrolyte homeostasis. Adult mammals subjected to manipulations that threaten homeostasis increase circulating renin by increasing the number of renin-expressing/-releasing cells. We hypothesize that the ability of adult cells to synthesize renin does not occur randomly in any cell type, depending instead on the cell's lineage. To determine the fate of renin-expressing cells, we generated knockin mice expressing cre recombinase in renin-expressing cells and crossed them with reporter mice. Results show that renin-expressing cells are precursors for a variety of cells that differentiate into non-renin-expressing cells such as smooth-muscle, epithelial, mesangial, and extrarenal cells. In the kidney, these cells retain the capability to synthesize renin when additional hormone is required to reestablish homeostasis: specific subpopulations of apparently differentiated cells are "held in reserve" to respond (repeatedly) by de-differentiating and expressing renin in response to stress, and re-differentiating when the crisis passes.

Animals↗
PubMed2004

The role of angiotensin II in kidney embryogenesis and kidney abnormalities.

PURPOSE OF REVIEW: The renin-angiotensin system has a major role in the control of blood pressure and homeostasis balance. It also plays a fundamental role in kidney development. Recent insights into how the angiotensin-generating cascade controls developmental processes and homeostasis, and, when defective, causes disease, are discussed. RECENT FINDINGS: The role of the renin-angiotensin system in kidney development is now widely accepted. New findings discussed in this review include the discovery of the capacity of the kidney to produce its own blood cells simultaneously with in-situ blood vessel formation, a process referred to as hemo-vasculogenesis. In addition, the role of the renin-angiotensin system in hematopoiesis is reviewed. Also discussed are the effects of angiotensin on branching morphogenesis and the development of hypertension in the adult as a result of a reduction in nephron number during nephrogenesis. Furthermore, the relationship between angiotensin and transdifferentiation of epithelial cells into fibroblasts is described. SUMMARY: The aforementioned advances help to clarify pathological processes such as extramedullary hematopoiesis, post-transplant erythrocytosis, the relationship between nephron number and hypertension, and the role of angiotensin and other growth factors in renal fibrosis. The molecules and pathways whereby angiotensin contributes to the processes mentioned above are beginning to be elucidated.

Angiotensin II↗
PubMed2003

Ablation of renin-expressing juxtaglomerular cells results in a distinct kidney phenotype.

Renin-expressing cells are peculiar in that they act as differentiated cells, producing the hormone renin, while they also seem to act as progenitors for other renal cell types. As such, they may have functions independent of their ability to generate renin/angiotensin. To test this hypothesis, we ablated renin-expressing cells during development by placing diphtheria toxin A chain (DTA) under control of the Ren1d mouse renin promoter by homologous recombination in a two-renin gene strain (Ren2 and Ren1d). Renin-expressing cells are essentially absent from kidneys in homozygotes (DTA/DTA) which, unlike wild-type mice, are unable to recruit renin-expressing cells when homeostasis is threatened. In contrast, renin staining in the submandibular gland (SMG), which expresses mainly Ren2, is normal. Homozygous mice survive normally, but the kidneys are small and have morphological abnormalities: 25% of the glomeruli are hyperplastic or atrophic, tubules are dilated and atrophic, and areas of undifferentiated cells exist near the atrophic glomeruli and tubules. However, in contrast to the very abnormal renal vessels found when renin-angiotensin system genes are deleted, the kidney vessels in homozygotes have normal wall thickness and no decrease in lumen size. Homozygotes have severely reduced kidney and plasma renin concentrations and females have reduced blood pressure. Homozygotes have elevated blood urea nitrogen and potassium levels, which are suggestive of altered renal function. We conclude that renin cells per se are necessary for the morphological integrity of the kidney and may have a role in maintenance of normal kidney function.

Animals↗
PubMed2002

The embryo makes red blood cell progenitors in every tissue simultaneously with blood vessel morphogenesis.

During embryonic life, hematopoiesis occurs first in the yolk sac, followed by the aorto-gonado-mesonephric region, the fetal liver, and the bone marrow. The possibility of hematopoiesis in other embryonic sites has been suspected for a long time. With the use of different methodologies (transgenic mice, electron microscopy, laser capture microdissection, organ culture, and cross-transplant experiments), we show that multiple regions within the embryo are capable of forming blood before and during organogenesis. This widespread phenomenon occurs by hemo-vasculogenesis, the formation of blood vessels accompanied by the simultaneous generation of red blood cells. Erythroblasts develop within aggregates of endothelial cell precursors. When the lumen forms, the erythroblasts "bud" from endothelial cells into the forming vessel. The extensive hematopoietic capacity found in the embryo helps explain why, under pathological circumstances such as severe anemia, extramedullary hematopoiesis can occur in any adult tissue. Understanding the intrinsic ability of tissues to manufacture their own blood cells and vessels has the potential to advance the fields of organogenesis, regeneration, and tissue engineering.

Animals↗
PubMed2002

A genetically clamped renin transgene for the induction of hypertension.

Experimental analysis of the effects of individual components of complex mammalian systems is frequently impeded by compensatory adjustments that animals make to achieve homeostasis. We here introduce a genetic procedure for eliminating this type of impediment, by using as an example the development and testing of a transgene for "genetically clamping" the expression of renin, the major homeostatically responding component of the renin-angiotensin system, one of the most important regulators of blood pressure. To obtain a renin transgene whose expression is genetically clamped at a constant level, we have used single-copy chosen-site gene targeting to insert into a liver-specific locus a single copy of a modified mouse renin transgene driven by a liver-specific promoter/enhancer. The resulting transgene expresses renin ectopically at a constant high level in the liver and leads to elevated plasma levels of prorenin and active renin. The transgenic mice display high blood pressure, enhanced thirst, high urine output, proteinuria, and kidney damage. Treatment with the angiotensin II type I receptor antagonist, losartan, reduces the hypertension, albuminuria, and kidney damage, but does not affect expression of the transgene. This genetically clamped renin transgene can be used in models in which hypertension and its complications need to be investigated in a high prorenin/renin environment that is not subject to homeostatic compensations by the animal when other factors are changed.

Animals↗
PubMed2002

Effects of AT(1A) receptor deletion on blood pressure and sodium excretion during altered dietary salt intake.

The present study was performed to investigate the role of type 1A ANG II (AT(1A)) receptors in regulating sodium balance and blood pressure maintenance during chronic dietary sodium variations in AT(1A) receptor-deficient (-/-) mice. Groups of AT(1A) (-/-) and wild-type mice were placed on a low (LS)-, normal (NS)-, or high-salt (HS) diet for 3 wk. AT(1A) (-/-) mice on an LS diet had high urinary volume and low blood pressure despite increased renin and aldosterone levels. On an HS diet, (-/-) mice demonstrated significant diuresis, yet blood pressure increased to levels greater than control littermates. There was no effect of dietary sodium intake on systolic blood pressures in wild-type animals. The pressure-natriuresis relationship in AT(1A) (-/-) mice demonstrated a shift to the left and a decreased slope compared with wild-type littermates. These studies demonstrate that mice lacking the AT(1A) receptor have blood pressures sensitive to changes in dietary sodium, marked alterations of the pressure-natriuresis relationship, and compensatory mechanisms capable of maintaining normal sodium balance across a wide range of sodium intakes.

Aldosterone↗
PubMed1996

Accumulation of acidic renin isoforms in kidneys of cyclosporine-A-treated rats.

Chronic cyclosporin A (CsA) treatment results in major hemodynamic changes in the renal microvasculature and in expression of the intrarenal renin angiotensin system. Changes in renin expression in kidneys of CsA-treated rats include the recruitment of immunoreactive renin in afferent arterioles and in the juxtaglomerular apparatus. This study presents evidence that an acidic isoform of renin is increased in kidneys of CsA-treated rats. Immunoblots of rat kidney homogenate separated by polyacrylamide-gel electrophoresis and also by isoelectric focusing demonstrate the presence of an acidic isoform (pl 5.5 and estimated molecular weight of approximately 32 to 36 kd) seen in increased amounts in kidney homogenate from CsA-treated rats. Silver-stained two-dimensional gels of renin separated from kidney homogenate with pepstatin agarose confirm the presence of an acidic renin isoform in CsA-treated rats. In rats that received CsA for varied intervals of 1, 3, 5, and 8 wk, this acidic isoform is shown to significantly accumulate relative to duration of treatment with CsA when immunoreactive bands are analyzed by densitometric scanning (r2 = 0.90, P < 0.001). Renin enzymatic activity also increased in kidney homogenate of CsA-treated rats relative to duration of treatment with CsA (r2 = 0.486, P < 0.001). Prorenin in these same samples was significantly decreased compared with controls. The acidic renin isoform identified in kidney homogenate of CsA-treated rats may be involved in the vascular changes that are seen in this model.

Acids↗
PubMed1987

Fetal expression of muscle-specific isoactins in multiple organs of the Wistar-Kyoto rat.

Actin, a cytoskeletal and contractile protein, is expressed in six different isoforms that exhibit striking specificity. No studies have considered the muscle-specific actin expression in multiple organ systems in the intact fetus. Using a monoclonal antibody (B4) which reacts specifically with the isoactins of the smooth and skeletal muscle our immunohistochemical study examined whole fetal body sections to follow the development of actin expression throughout the last third of gestation in the Wistar-Kyoto rat. B4 staining was exclusively localized to muscle, confirming its high specificity and its usefulness for studying the ontogeny of muscle-specific isoactins. At 15 days of gestation, B4 staining was detected in the heart, the thoracic aorta and the skeletal muscle of the chest wall. The distribution and intensity of staining in the heart were initially higher than in the aorta or skeletal muscle and remained unchanged throughout the remainder of gestation, suggesting that the maturation of cardiac actin expression is well developed, although not fully completed before birth. Expression of muscle-specific actins in skeletal muscle was age-dependent and correlated with the maturational changes of muscle cell precursors. B4 staining in the fetal kidney was not apparent until day 20 of gestation and was localized to the inner cortical vessels. in association with the most mature nephrons, suggesting a centrifugal maturation of the intrarenal vasculature. The intensity of B4 staining in most tissues including bronchi, bowel, diaphragm, chest wall muscle and peripheral and pulmonary arteries increased by the end of gestation.

Actins↗