Browsing by Author "VIO, CP"

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    CELLULAR MECHANISMS OF ESTROGEN-INDUCED AND DOPAMINE-INDUCED CONTROL OF GLANDULAR KALLIKREIN IN THE ANTERIOR-PITUITARY OF THE RAT
    (1993) ROA, JP; POWERS, CA; SILVA, R; VIO, CP
    Glandular kallikrein (GK, a trypsin-like serine protease) exhibits estrogen induction and dopamine repression in rat pituitary lactotrophs. Steroid induction may reflect primary actions to increase selectively the synthesis of specific proteins, or may be part of broad cellular responses secondary to steroid-induced phenotype transitions. This study examined the cellular mechanisms underlying estrogen and dopaminergic control of lactotroph GK using a quantified immunocytochemical approach. Pituitaries from ovariectomized rats exhibited little GK staining. Estradiol treatment for 10 days produced dose-dependent increases in pituitary mass, the percentage of lactotrophs (indicating lactotroph proliferation) and the percentage of GK-positive cells. Also, GK staining intensity was dependent upon estradiol dose, increasing 4-fold between 5 mu g and 50 mu g/48 h. Dopamine receptor blockade with haloperidol (2.5 mg/kg/24 h) elicited weak GK immunostaining in 46% of the lactotrophs in the absence of estradiol, and markedly potentiated GK staining intensity elicited with low but not high doses of estradiol. The results suggest that GK induction is a primary estrogen effect, and is not secondary to a phenotype transition: the induction is enhanced by estrogen-induced lactotroph proliferation. Dopaminergic systems strongly inhibit GK induction by low estradiol levels. This dopaminergic modulation may shift the induction of lactotroph GK to physiological events associated with high estradiol levels or low dopaminergic tone.
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    DECREASED KALLIKREIN EXCRETION IN RENAL-TRANSPLANT TREATED WITH CYCLOSPORINE-A
    (APPLETON & LANGE, 1990) MARTINEZ, L; VIO, CP; VALDES, G; KYCHENTHAL, W; MENDOZA, S
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    EVIDENCE FOR A STIMULATORY EFFECT OF HIGH POTASSIUM DIET ON RENAL KALLIKREIN
    (1987) VIO, CP; FIGUEROA, CD
    Considerable evidence indicates that the connecting tubule cells, a type of the distal nephron which seems to participate on potassium secretion, may be the place where renal kallikrein is synthetized. As potassium secretion and kallikrein synthesis may occur in the same cells, we studied the effect of high potassium diet on renal kallikrein production. The kallikrein containing cells from rats fed a normal and high potassium diet were evaluated using a combination of morphometric analysis, conventional electron microscopy, and ultrastructural immunocytochemistry. High potassium diet produced hypertrophy and hyperplasia of the kallikrein containing cells. Hyperplasia was sustained by an increased number of immunoreactive cells/mm2 (151 .+-. 14 vs. 86.4 .+-. 12, P < 0.01), an increased number of binucleated immunoreactive cells/mm2 (11.90 .+-. 2.1 vs. 3.77 .+-. 0.17, P < 0.005), and by the presence of mitosis. Cell hypertrophy was sustained by an increased cross-sectional area of immunoreactive cells (.mu.2) (320.4 .+-. 21 vs. 104.5 .+-. 6.1, P < 0.001), by an increased area of basal plasma membrane infoldings, by an hypertrophy of the components of the Golgi complex, hypertrophy of the components of the rough endoplasmic reticulum, and by a larger number of secretory-like vesicles containing kallikrein. The rats fed with high potassium diet had higher values on urinary kallikrein excretion-amidase activity (3.70 .+-. 0.51 vs. 2.01 .+-. 0.37 units/day, P < 0.02), higher values on potassium excretion (18.8 .+-. 17 vs. 1.31 .+-. 0.1 mmol/day, P < 0.001), and higher urinary volume (51.5 .+-. 5.3 vs. 12.2 .+-. 1.6 ml/day, P < 0.001). The increased size of the kallikrein containing cells correlated with kallikrein excretion (r = 0.7013, P < 0.002). These results suggest that high potassium diet stimulates the kallikrein containing cells of the distal nephron producing hyperplasia and hypertrophy. Taken the ultrastructural changes together with the increased urinary excretion of kallikrein, the results suggest that a high potassium diet increased the synthesis and secretion of kallikrein. The nature of this stimulatory effect cannot be elucidated from the present study.
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    EVIDENCE FOR RENAL KININS AS MEDIATORS OF AMINO-ACID INDUCED HYPERPERFUSION AND HYPERFILTRATION IN THE RAT
    (1992) JAFFA, AA; VIO, CP; SILVA, RH; VAVREK, RJ; STEWART, JM; RUST, PF; MAYFIELD, RK
    This study examined the role of tissue kallikrein and kinins in renal vasodilation produced by infusion of amino acids (AA). In rats fed a 9% protein diet for 2 wk, intravenous infusion of a 10% AA solution over 60-90 min reduced total renal vascular resistance and increased glomerular filtration rate (GFR) by 25-40% and renal plasma flow (RPF) by 23-30% from baseline. This was associated with a two- to threefold increase in urinary kinin excretion rate. Acute treatment of rats with aprotinin, a kallikrein inhibitor, resulted in deposition of immunoreactive aprotinin in kallikrein-containing connecting tubule cells and inhibited renal kallikrein activity by 90%. Aprotinin pretreatment abolished the rise in urinary kinins and prevented significant increases in GFR and RPF in response to AA. In a second group of rats pretreated with a B2 kinin receptor antagonist, [DArg Hyp3, Thi5.8 D Phe7] bradykinin, AA infusion raised urinary kinins identically as in untreated controls, but GFR and RPF responses were absent. Aprotinin or the kinin antagonist produced no consistent change in renal function in rats that were not infused with AA.AA-induced increases in kinins were not associated with an increase in renal kallikrein activity. Notably, tissue active kallikrein level fell 50% in AA-infused rats. These studies provide evidence that kinins generated in the kidney participate in mediating renal vasodilation during acute infusion of AA.
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    KALLIKREIN EXCRETION - RELATIONSHIP WITH MATURATION AND RENAL-FUNCTION IN HUMAN NEONATES AT DIFFERENT GESTATIONAL AGES
    (1987) VIO, CP; OLAVARRIA, F; KRAUSE, S; HERRMANN, F; GROB, K
    Kallikrein excretion and renal function were studied on 37 one-day-old newborn infants (14 fullterm and 23 preterm infants). Preterm infants excreted less kallikrein (p < 0.001), had lower creatinine clearance (p < 0.02) and urinary osmolality (p < 0.01). They had higher values on urinary volume (p < 0.001), FENa (p < 0.001), FEk (p < 0.02), and free water clearance (p < 0.01) than fullterm infants. The excretion of kallikrein correlated directly with gestational age (p < 0.01) and body weight (p < 0.01). No correlations were found with FENa, urinary volume, FEk or free water clearance. The values of kallikrein excretion were very low when compared with a young adult population. As kallikrein is synthesized in the distal nephron we advance as an hypothesis that the low levels of kallikrein excretion observed in newborns could be a reflection of immature distal tubular mass, and to the relative unresponsiveness of the distal nephron to hormones known to stimulate renal kallikrein such as aldosterone and antidiuretic hormone.
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    KALLIKREIN-KININ AND RENIN-ANGIOTENSIN SYSTEMS IN RENOVASCULAR HYPERTENSION IN RATS
    (1980) VIO, CP; ROBLERO, JS; CROXATTO, HR
    Plasma renin activity (PRA) and the levels of urinary kallikrein (UK) were studied simultaneously in Goldblatt 1- and 2-kidney hypertensive rats (1KG and 2KG) 5, 10 and 15 wk after clamping the left renal artery. Increase in PRA was statistically significant in 2KG rats (P < 0.0005 on the 5th and 10th wk, and P < 0.002 on the 15th wk). PRA was not significantly different to that of controls in 1KG rats. The urinary kallikrein levels were significantly lower in 1KG rats (P < 0.002) in relation to values found in normotensive rats. In 2KG rats, urinary kallikrein levels became significantly lower than those in controls only 15 wk after surgery.
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    LOCALIZATION OF IMMUNOREACTIVE GLANDULAR KALLIKREIN IN LACTOTROPHS OF THE RAT ANTERIOR-PITUITARY
    (1990) VIO, CP; ROA, JP; SILVA, R; POWERS, CA
    Glandular kallikrein (a trypsin-like serine protease) is an estrogen-induced and dopamine-repressed protein in the rat anterior pituitary which predominantly exists as a latent zymogen (prokallikrein). Its regulation, presence in estrogen-induced pituitary tumors in F344 rats, and expression in GH3 cells has suggested a localization in lactotrophs (prolactin-producing cells). This study examined the cellular origin of glandular kallikrein using immunocytochemical techniques. Anterior pituitaries from estrogen-treated rats were fixed and embedded in paraffin (for preparation of semi thick sections; 5 .mu.m) or methacrylate (for preparation of thin sections; 1 .mu.m). Glandular kallikrein immunostaining was readily detected in the perinuclear (Golgi) region of parenchymal cells of the anterior pituitary in both thin and semi thick sections. Two-color double immunoperoxidase staining of thin and semi thick sections indicated that glandular kallikrein was localized in cells containing prolactin (PRL) but not other pituitary hormones. Immunoperoxidase staining of consecutive serial thin sections with alterating antisera confirmed a localization of glandular kallikrein in lactotrophs. The results establish that glandular kallikrein is colocalized with PRL in lactotrophs of the rat anterior pituitary. This is consistent with the hypothesis that the function of anterior pituitary glandular kallikrein is linked to PRL in some fashion-possibly as a PRL-processing protease.
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    POSTNATAL MATURATION OF TISSUE KALLIKREIN-PRODUCING CELLS (CONNECTING TUBULE CELLS) IN THE RAT-KIDNEY - A MORPHOMETRIC AND IMMUNOHISTOCHEMICAL STUDY
    (1995) VELARDE, V; HUMPHREYS, J; FIGUEROA, CD; VIO, CP
    The mature, fully differentiated connecting tubule (CNT) cell plays an important role in the regulation of serum potassium levels and synthesizes the enzyme tissue kallikrein, a main component of a renal vasoactive system, the kallikrein-kinin system. To characterize the growth of CNT cells (tissue kallikrein-producing cells), we studied the rat kidney at three different time points of postnatal development: at day 5, day 15, and day 30. The CNT cells were identified on tissue sections by a standardized immunohistochemical procedure. The tissue kallikrein content was determined by radioimmunoassay and the activity of the enzyme in kidney homogenates was measured using a selective synthetic substrate. The number of immunolabeled CNT and CNT cells per cortex area gradually increased from day 5 to day 30. A similar rise in the content and activity of tissue kallikrein was observed when the enzyme levels were determined by radioimmunoassay or by the enzymatic method. In addition, the morphometric analysis showed that the distal end of CNT had larger cells that displayed a more intense tissue kallikrein staining than those present in the proximal end, suggesting that the postnatal development of CNT is induced from its juxtamedullary portion. Our results show that tissue kallikrein expression is very low in the newborn rat, increasing gradually with age to reach adult levels at day 30. This finding, together with the morphometric data, suggests immaturity of CNT cells in newborn rats, a fact that could contribute to explaining the high serum potassium levels reported at this stage. In addition, the contrasting behavior of kallikrein and renin in the postnatal development (kallikrein increasing and renin decreasing) could explain the gradual decrease in renal vascular resistance and increase in renal blood flow observed after birth.
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    POTASSIUM SUPPLEMENTATION LOWERS BLOOD-PRESSURE AND INCREASES URINARY KALLIKREIN IN ESSENTIAL HYPERTENSIVES
    (1991) VALDES, G; VIO, CP; MONTERO, J; AVENDANO, R
    In order to eludicate possible mechanism(s) involved in the blood pressure reduction induced by potassium (K) supplementation, we studied the changes of BP and of some of its regulatory systems, including levels of urinary kallikrein (UKal)-an index of renal kallikrein production. Twenty-four untreated essential hypertensives, with a basal BP of 147/96 +/- 13/7 mmHg and normal renal function, received in crossover, double-blind, randomised fashion, 64 mmol KCl or placebo during two periods of 4 weeks each. At the 4th week of potassium supplementation systolic, diastolic and mean BPs decreased by 6.3 +/- 2 (P < 0.01), 3.0 +/- 2 and 4.1 +/- 2 (P < 0.05) mmHg respectively for the supine position, and 5.0 +/- 2, 4.0 +/- 2 (P < 0.05) and 4.0 +/- 1 (P < 0.05) mmHg for the standing position. Urinary potassium (K) increased from 55 +/- 4 to 123 +/- 6 mmol/24 hours (P < 0.001) and UKal from 692 +/- 69 to 1052 +/- 141 mU/24 hours (P < 0.01). Serum K rose from 3.8 +/- 0.1 mEq/l to 4.1 +/- 0.1 mmol/l (P < 0.001) and PRA from 0.77 +/- 0.12 to 0.99 +/- 0.14 ng/ml/h (P < 0.05). Correlations were observed between UKal and urinary K (r = 0.44, P < 0.0001); between differences in UKal and urinary K and in UKal and urinary Na (r = 0.50, P < 0.0005 and r = 0.48, P < 0.001 respectively). Responders to KCl supplementation (n = 7) had a greater increase of urinary kallikrein (P < 0.005) and PRA (P < 0.05) than nonresponders (n = 8). The present study confirms the mild BP lowering effect and stimulation of UKal by KCl supplementation and shows that variations in UKal correlate with urinary K and characterise patients with potassium sensitivity. Further studies, that include determinations of the circulating components of the kallikrein-kinin system, are required to elucidate whether bradykinin, the enzymatic product of kallikrein and potent stimulator of endothelial protective factors, may be a mediator of the vascular effects described for a high K intake.