Metabolic heterogeneity of isolated cortical and juxtamedullary glomeruli in adriamycin nephrotoxicity.

The anticancer drug adriamycin (ADR) is selectively toxic to glomerular cells when administered intravenously (5 mg/kg b.w.) to female MWF/Ztm rats. Recent data have shown that the proteinuria associated with the lesion does not occur in cortical glomeruli, suggesting the selective injury of juxtamedullary glomeruli. In the present study, the effect of ADR on glomerular metabolism was studied with special reference to possible differences between cortical and juxtamedullary glomeruli. On day 7 after ADR treatment, cortical and juxtamedullary glomeruli were separately isolated by the sieving method and 14C glucose oxidation to 14CO2 and the incorporation of 3H proline into macromolecules were measured in vitro and used to study target selective injury in ADR-treated rats compared to control rats. The investigations revealed differences in the response of cortical and juxtamedullary glomeruli to ADR. ADR treatment increased proline incorporation over a 4-hour incubation period in both glomerular populations compared to controls, but the effect was significantly (p less than 0.05) more pronounced in juxtamedullary glomeruli (juxtamedullary: 187 +/- 8% of control; cortical: 167 +/- 4% of control). Glucose oxidation was enhanced after 4 h only in juxtamedullary glomeruli (juxtamedullary: 132 +/- 3% of control; cortical: 82 +/- 10% of control). These data show that glomerular damage caused by ADR is associated with a stimulating effect on glomerular metabolism which is more marked in juxtamedullary than in cortical glomeruli, thus indicating a heterogenous response of different glomerular populations and supporting the concept that the selective damage of juxtamedullary glomeruli accounts for the proteinuria.     

Gross and microscopic anatomy of the kidney of the West Indian manatee, Trichechus manatus (Mammalia: Sirenia)

Examination of the gross and microscopic anatomy of the kidney of the West Indian manatee, Trichechus manatus, revealed that: (1) the medulla is about 6 times thicker than the cortex; (2) juxtamedullary glomeruli have a mean diameter 1.3 times greater than that of cortical glomeruli; (3) juxtamedullary glomeruli have 1.7 times as much volume as cortical glomeruli; (4) there are about twice as many cortical glomeruli as juxtamedullary glomeruli per square millimeter of cortical tissue, and (5) the vasa recta are closely juxtaposed to the thin loops of Henle in the outer medulla. Many of these results suggest an enhanced urine-concentrating ability in this species.     

Repartition of the kidney cortex glomerulus in rats]

This paper presents the repartition of 989 glomeruli in 8 parallel concentric renal cortex zones, by projecting on a calibrated screen rat kidney slices photographies. The glomerular density increases regularly from the outside to the middle cortical zones and then decreases to the deepest juxtamedullary zones.     

Morphometry of the renal corpuscle during normal postnatal growth and compensatory hypertrophy. A light microscope study

Renal corpuscles from the juxtamedullary and subcapsular regions of the renal cortex were morphometrically analyzed in young rats and in adult rats that had been unilaterally nephrectomized or sham-operated at an early age. Mean corpuscular volumes increased 4.5-fold during normal development, and 7.7-fold as a result of compensatory hypertrophy in both cortical regions. Relative and absolute volumes were determined for Bowman's space, the glomerular tuft, and five glomerular components: epithelial, endothelial, and mesangial cells, capillaries, and the filtration membrane. Normal and hypertrophic enlargement of Bowman's space was slightly greater than glomerular growth, and the growth response of subcapsular glomeruli was greater than that of juxtamedullary glomeruli. The ratio of mean glomerular volumes between outer and inner glomeruli was 1:2 in both adult groups. Both adult groups also developed nearly identical proportions of all glomerular component structures, representing a relative decrease of epithelial cells and increase of capillaries compared to the young animals. Normal and hypertrophic maturation involved absolute increases in all glomerular cell populations, the length of capillary loops and the surface area of the filtration membrane, all nearly in proportion to the respective four- and seven-fold increases in glomerular volume. Changes in the filtration surface area are consistent with published data for glomerular filtration rates in normal and hypertrophied kidneys. The mean cell size in epithelial and mesangial populations doubled during growth, but was not greater than normal in mononephrectomized rats. Hyperplasia among all populations of glomerular cells is indicated in normal growth, and to a greater extent in compensatory renal hypertrophy.     

Morphofunctional characteristics of the intrinsic arterial vessels of the kidney in healthy subjects and in various cardiovascular diseases

The investigation has been performed in 132 kidneys of corpses of persons at various ages, 96 of them died from some cardiovascular diseases and 36--from mechanical asphyxia. Injection, macro-microscopical, histological, biometrical and variational-statistic methods have been used. The total section areas of the arterial vessels is determined, it characterizes the vascular bed capacity of the renal cortical and medullary parts. At atherosclerosis, hypertension and cardiac ischemia an essential decrease in the vascular bed capacity in the cortical part and its increase in the medullary part of the kidney is observed. An increasing diameter of the juxtamedullary glomeruli is supposed to intensify the juxtamedullary blood stream. The greatest changes in architectonics and capacity of the renal arterial bed is observed at hypertension combined with atherosclerosis, and the least--at a chronic cardiac ischemia.     

Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.     

Ontogeny of atrial natriuretic peptide receptors in fetal rat kidney and adrenal gland

With in vitro autoradiography, specific receptors for atrial natriuretic peptide (ANP) were localized in fetal rat kidney and adrenal glands. Receptors were present over renal vesicles, in the primitive renal medulla and throughout the adrenal gland as early as 16 days gestation. By 20 days gestation, several layers of developing renal corpuscles were present and ANP receptors were localized over developing glomeruli in each layer. Larger accumulations occurred over the juxtamedullary glomeruli. In the medulla, the receptors were localized in a reticular pattern near the pelvis. With emulsion coated sections, ANP receptors in developing renal corpuscles were seen primarily over the lower curve of S-shaped vesicles and around the periphery of the more mature corpuscles. In the renal medulla, receptors were localized over the interstitial cells. In the 16-day-old adrenal gland, ANP receptors were present throughout the cortical area but at 20 days gestation and 1 day postpartum receptors appeared more numerous in the peripheral region. These data suggest that ANP has important developmental effects in the kidney and adrenal gland and may be involved in regulation of body fluid homeostasis in the late gestation rat fetus.     

Ontogeny of atrial natriuretic peptide receptors in fetal rat kidney and adrenal gland

Summary With in vitro autoradiography, specific receptors for atrial natriuretic peptide (ANP) were localized in fetal rat kidney and adrenal glands. Receptors were present over renal vesicles, in the primitive renal medulla and throughout the adrenal gland as early as 16 days gestation. By 20 days gestation, several layers of developing renal corpuscles were present and ANP receptors were localized over developing glomeruli in each layer. Larger accumulations occurred over the juxtamedullary glomeruli. In the medulla, the receptors were localized in a reticular pattern near the pelivis. With emulsion coated sections, ANP receptors in developing renal corpuscles were seen primarily over the lower curve of S-shaped vesicles and around the periphery of the more mature corpuscles. In the renal medulla, receptors were localized over the interstitial cells. In the 16-day-old adrenal gland, ANP receptors were present throughout the cortical area but at 20 days gestation and 1 day postpartum receptors appeared more numerous in the peripheral region. these data suggest that ANP has important developmental effects in the kidney and adrenal gland and may be involved in regulation of body fluid homeostasis in the late gestation rat fetus.     

Zinc deficiency during growth: influence on renal function and morphology

This study was designed to investigate the effects of moderate zinc deficiency during growth on renal morphology and function in adult life. Weaned male Wistar rats were divided into two groups and fed either a moderately zinc-deficient diet (zinc: 8 mg/kg, n=12) or a control diet (zinc: 30 mg/kg, n=12) for 60 days. We evaluated: renal parameters, NADPH-diaphorase and nitric oxide synthase activity in kidney, renal morphology and apoptotic cells in renal cortex. Zinc-deficient rats showed a decrease in glomerular filtration rate and no changes in sodium and potassium urinary excretion. Zinc deficiency decreased NADPH diaphorase activity in glomeruli and tubular segment of nephrons, and reduced activity of nitric oxide synthase in the renal medulla and cortex, showing that zinc plays an important role in preservation of the renal nitric oxide system. A reduction in nephron number, glomerular capillary area and number of glomerular nuclei in cortical and juxtamedullary areas was observed in zinc deficient kidneys. Sirius red staining and immunostaining for alpha-smooth muscle-actin and collagen III showed no signs of fibrosis in the renal cortex and medulla. An increase in the number of apoptotic cells in distal tubules and cortical collecting ducts neighboring glomeruli and, to a lesser extent, in the glomeruli was observed in zinc deficient rats. The major finding of our study is the emergence of moderate zinc deficiency during growth as a potential nutritional factor related to abnormalities in renal morphology and function that facilitates the development of cardiovascular and renal diseases in adult life.     

Angiotensin II receptors in the kidney

Angiotensin II (AngII) receptors have been localized in rat kidney by using the high-affinity agonist analog 125I-labeled [Sar1]AngII as a probe for in vitro autoradiography. Receptors were associated with four morphologically distinct patterns of distribution. First, a high density of receptors occurs in glomeruli. These are diffusely distributed, consistent with a mesangial localization. AngII receptor density shows a cortical gradient, which is highest in superficial and midcortical glomeruli and lowest in juxtamedullary glomeruli. Receptors associated with both superficial and deep glomeruli show down-regulation during low-sodium intake. Second, low levels of tubular AngII binding were seen in the outer cortex. Third, a very high density of AngII receptors occurs in longitudinal bands in the inner zone of the outer medulla in association with vasa recta bundles. Receptors in this site also show down-regulation during low dietary sodium intake. Fourth, a moderate density of receptors occurs diffusely throughout the inner zone of the outer medulla in the interbundle areas. These results suggest that AngII exerts a number of different intrarenal regulatory actions. In addition to the known vascular, glomerular, and proximal tubular effects of AngII, these findings focus attention on possible actions of AngII in the renal medulla where it could regulate medullary blood flow and thereby modify the function of the countercurrent concentrating system.     

Development of various nephron populations in birds during ontogenesis

Microanatomy of nephrons during ontogenesis has been studied in domestic hens. In the bird kidneys, as well as in mammalian kidneys, three populations of nephrons can be detected: juxtamedullary, or deep nephrons, superficial and situating between them intracortical nephrons. In formation of the bird renal medulla only loops of the juxtamedullary nephrons participate. During ontogenesis in the kidneys of birds, like in mammalians, juxtamedullary nephrons are the first to be formed; they can be obtained from kidneys of 14-day-old chicken embryos, however, a complete formation of the nephron structure is terminated after hatching. During development the length of the juxtamedullary nephrons increases nearly by one order, while the length of the superficial and intracortical nephrons increases no more than twice. The diameter of the glomeruli in the juxtamedullary nephrons during development increases nearly twice, in the superficial and intracortical nephrons only a slight increase is noted. A relative length of the proximal canaliculus of the intracortical and superficial nephrons gradually increases during ontogenesis and practically does not change in the juxtamedullary nephrons, in them the nephron loop becomes longer. The developmental pattern in various parts of the superficial, intracortical and juxtamedullary nephrons in general features is similar in mammalians and birds.     

Cardiac edema in dogs: distribution of renal blood flow and glomerular filtrate.

The injection of Freund's adjuvant into the pericardial sac of 29 dogs resulted in chronic pericardial tamponade with persistent sodium retention. Micropuncture, clearance, and radioactive microsphere experiments were initiated 6--13 days after pericardial injection and 60 min after pericardiocentesis. Pericardiocentesis increased sodium excretion (from 12.2 to 41.3 microequiv./min) and mean arterial pressure (+ 20 mmHg (1 mmHg = 133.322 Pa)). Central venous pressure decreased 6.5 mmHg, as did hematocrit (from 45.7 to 39.8%) and plasma protein concentration (from 5.88 to 5.15 g%). Pericardiocentesis had no significant effect on renal blood flow (RBF), nor plasma flow. Redistribution of glomerular filtrate was suggested by the observation that superficial nephron glomerular filtration rate increased (from 91 to 108 nL/min) while glomerular filtration rate remained unaltered. Determination of intrarenal distribution of RBF revealed that cortical blood flow also distributed superficially. A significant increase in the fraction of RBF perfusing zone 1 (outer cortex) and a decrease in fractional perfusion of zones 2, 3 and 4 (juxtamedullary cortex) were observed in each experiment following pericardiocentesis. RBF distribution examined in a series of six animals prior to and during the development of pericardial tamponade showed the opposite effect. These results indicate that pericardiocentesis causes redistribution of both glomerular filtrate and RBF to superficial nephrons. The development of pericardial tamponade was associated with increased fractional juxtamedullary blood flow. These changes may have been the result of altered blood pressure, hematocrit, plasma protein concentration, or altered renal resistance.     

Tomographical description of tennis-loaded radius: reciprocal relation between bone size and volumetric BMD.

Effects of long-term tennis loading on volumetric bone mineral density (vBMD) and geometric properties of playing-arm radius were examined. Paired forearms of 16 tennis players (10 women) and 12 healthy controls (7 women), aged 18-24 yr, were scanned at mid and distal site by using peripheral quantitative computerized tomography. Tomographic data at midradius showed that tennis playing led to a slight decrease in cortical vBMD (-0.8% vs. nonplaying arm, P < 0. 05) and increase both in periosteal and endocoritcal bone area (+15. 2% for periosteal bone, P < 0.001; and +18.8% for endocortical bone, P < 0.001). These data suggest that, together with an increase in cortical thickness (+6.4%, P < 0.01), cortical drift toward periosteal direction resulted in improvement of mechanical characteristics of the playing-arm midradius. Enlargement of periosteal bone area was also observed at distal radius (+6.8%, P < 0.01), and the relative side-to-side difference in periosteal bone area was inversely related to that in trabecular vBMD (r = -0.53, P < 0.05). We conclude that an improvement of mechanical properties of young adult bone in response to long-term exercise is related to geometric adaptation but less to changes in vBMD.     

Heterogeneity of glomerular barrier function in early adriamycin nephrosis of MWF rats

Adriamycin (ADR), selectively toxic to glomerular epithelial cells, was administered (5 mg/kg BW, i.v.) to MWF/Ztm rats to study its early effects on glomerular barrier function with respect to albumin and high molecular weight (HMW) proteins. After 7 days of ADR incubation (glomerular filtration rate remains unchanged), protein excretion was significantly increased in treated rats. The proteinuria was due to a nonselective glomerular lesions resulting in an increase in both, but not a changed ratio of HMW proteins to albumin. However, this ADR-induced proteinuria seen in the final urine was not confirmed by free-flow micropuncture studies of superficial glomeruli. The albumin and HMW protein concentrations in samples taken from Bowman's capsular space of ADR-treated rats did not significantly differ from control samples. These data suggest that cortical nephrons are less sensitive to ADR than juxtamedullary nephrons.     

Involvement of Dopamine Neurons in the Regulation of β-Adrenergic Receptor Sensitivity in Rat Prefrontal Cortex

The contribution of dopamine (DA) afferents to the regulation of beta-adrenergic receptor sensitivity (isoproterenol-stimulated adenylate cyclase activity) in the rat prefrontal cortex was investigated by comparing the effects of lesions affecting either both DA and noradrenaline (NA) or NA fibers alone. Bilateral 6-hydroxydopamine (6-OHDA) lesions made in the ventral tegmental area destroyed ascending DA and to a variable extent ascending NA fibers innervating the prefrontal cortex. Two opposite effects were observed depending on the extent of cortical NA denervation: (a) When NA denervation was complete (less than 4% of controls), a marked increase in the isoproterenol-sensitive adenylate cyclase activity (+78%) was found. The amplitude of this denervation supersensitivity was similar to that occurring following complete and selective destruction of NA innervation induced by bilateral 6-OHDA injections made into the pedunculus cerebellaris superior. (b) When 6-OHDA injections into the ventral tegmental area led to a partial destruction of cortical NA afferents (10-40% of control values), a hyposensitivity of the isoproterenol-induced adenylate cyclase activity (-30%) was observed. This effect contrasted with the moderate supersensitivity seen in rats with partial, but selective, destruction of NA innervation (pedunculus cerebellaris superior lesions). The hyposensitivity of beta-adrenergic receptors obtained in rats with partial lesions of cortical NA fibers, but devoid of cortical DA innervation, suggests that DA neurons may regulate, under certain conditions, the denervation supersensitivity of beta-adrenergic receptors.     

Influence of 3 beta-blockers on the diameter of glomeruli isolated from the renal cortex of rats

The purpose of the study was to determine a direct vascular effect of beta-blockers on isolated glomeruli of rat kidney. The glomeruli were isolated by sieving and their diameters measured with a micrometer before and after addition of each of three beta-blockers. The diameter of the glomeruli increases (6,7%) with verapamil, a calcium inhibitor, but remains unchanged in the same experimental conditions as well with propranolol, drug which decreases renal plasma flow, than with nadolol and tertatolol, drug increasing renal haemodynamics. The location and the mechanism of the glomerular vasoactivity of these different beta-blockers are discussed.     

Tissue localization of the copper chaperone ATOX1 and its potential role in disease

ATOX1 is a cytoplasmic copper chaperone that interacts with the copper-binding domain of the membrane copper transporters ATP7A and ATP7B. ATOX1 has also been suggested to have a potential anti-oxidant activity. This study investigates the tissue-specific localization of the mouse homolog, Atox1, in mouse liver and kidney. Immunohistochemical studies in the liver localize the copper chaperone to hepatocytes surrounding both hepatic and central veins. In the kidney, Atox1 is localized to the cortex and the medulla. Cortex immunostaining is specific to glomeruli in both the juxtamedullary and cortical nephrons. Expression in the medulla appears to be associated with the loops of Henle. These data suggest that localized regions in the liver and kidney express Atox1 and have a role in copper homeostasis and/or anti-oxidant protection. Twenty-seven patients with Wilson disease-like phenotypes and two patients with Menkes disease-like phenotypes were screened for ATOX1 mutations with no alterations detected. The human phenotype resulting from mutations in ATOX1 remains unidentified.     

Aglomerular pathways in intrarenal microvasculature of aged rats

By means of silicone rubber injections, we confirmed the existence of several types of aglomerular arterial pathways within kidneys of aged rats. In superficial cortex some interlobular arteries divide to form aglomerular branches (Ludwig's arterioles) towards cortex corticis. In juxtamedullary cortex these pathways are relatively more numerous, they comprise: (a) Vasa Recta Vera, (b) glomeruli in which afferent and efferent arterioles form a continuous vessel and (c) glomeruli with two efferent vessels, one by-passing glomerular tuft. In addition, results obtained in the rat by the microsphere technique are in agreement with our morphological observations.     

Effect of acetazolamide on cerebral blood flow and capillary patency.

This study investigated the effects 2 h after administration of acetazolamide on cerebral blood flow and the pattern of cerebral capillary perfusion. Arterial blood pressure, heart rate, arterial blood gases, and pH were recorded in two groups of rats along with either regional cerebral blood flow or the percentage of capillary volume per cubic millimeter and number per square millimeter perfused as determined in cortical, thalamic, pontine, and medullary regions of the brain. Blood pressure, heart rate, and arterial PCO2 were not significantly different between the rats receiving acetazolamide (100 mg/kg) and the controls. Arterial blood pH was significantly lower in the acetazolamide rats. Blood flow increased significantly in the cortical (+ 102%), thalamic (+ 89%), and pontine (+ 88%) regions receiving acetazolamide. In control rats, approximately 60% of the capillaries were perfused in all of the examined regions. The percentage of capillaries per square millimeter perfused was significantly greater in the cortical (+ 52%), thalamic (+ 49%), and pontine (+ 47%) regions of acetazolamide rats compared with controls. In the medulla the increases in blood flow and percentage of capillaries perfused were not significant. Thus in the regions that acetazolamide increased cerebral blood flow, it also increased the percentage of capillaries perfused.     

The role of calcium in monoamine-induced depression of cerebral cortical neurones

The calcium antagonists, lanthanum, verapamil and manganese, have been shown to antagonize the depressant actions of ionto-phoretically applied monoamines (noradrenaline, 5-hydroxytryptamine, dopamine and histamine), but not of γ-aminobutyric acid, on cerebral cortical neurones. Cocaine and ethanol, which also affect membrane calcium fluxes, have a similar antagonistic action. These findings suggest that calcium ions are essential for, and perhaps mediate, the characteristic depressant actions of the monoamines on cerebral cortical neurones.