Elevated cytosolic calcium of adipocytes in chronic renal failure

Elevated cytosolic calcium of adipocytes in chronic renal failure. Chronic renal failure (CRF) is associated with increased calcium content of, and impaired lipase release from lipid cells. This has been attributed to a rise in the cytosolic calcium ([Ca2+]i) of these cells. However, data on [Ca2+]i of lipid cells in CRF and on the mechanisms responsible for such an abnormality are lacking. To study this issue we examined the [Ca2+]i and ATP content of lipid cells and Vmax of Na+-K+-ATPase and Ca2+ ATPase of membrane preparation and Na+-Ca2+ exchange of membrane vesicles of adipocytes from normal rats, 6 week CRF, CRF normocalcemic parathyroidectomized (CRF-PTX) and CRF, and normal rats treated with verpamil (CRF-V, normal-V). [Ca2+]i in adipocytes of CRF rats was higher (199 ± 8.5 nM) and ATP lower (2.9 ± 0.31 nmol/106 cells) than in normal (120 ± 4.3 nM; 5.7 ± 0.27 nmol/106 cells), CRF-PTX (128 ± 4.7 nM; 5.8 ± 0.39 nmol/106 cells), normal-V (121 ± 3.2 nM; 5.3 ± 0.36 nmol/106 cells), CRF-V (123 ± 7.4 nM; 5.5 ± 0.30 mnol/106 cells). Vmax Ca2+ATPase and the activity of Na+-K+-ATPase and of Na+-Ca2+ exchanger were reduced in CRF rats as compared to the other four groups of rats. The values in normal, CRF-PTX, CRF-V and normal-V rats were not different. These results indicate that: (1) in CRF, adipocytes are overloaded by calcium; (2) this abnormality is mediated by the secondary hyperthyroidism of CRF since PTX of CRF rats or interference with the action of PTH by a calcium channel blocker prevented these changes; and (3) the elevation in [Ca2+]i is due to both increased entry of calcium into adipocytes and a decreased extrusion out of these cells

Defects in B-cell function and metabolism in uremia: Role of parathyroid hormone

Defects in B-cell function and metabolism in uremia: Role of parathyroid hormone. Patients with chronic renal failure have impaired humoral immunity, inadequate B-cell proliferation and antibody production, and elevated basal levels of cytosolic calcium ([Ca2+]i) in their B cells. Multiple mechanisms can be involved in generation of these derangements. This article reviews data suggesting that high levels of parathyroid hormone (PTH) of uremia affect the metabolism and function of B cells. We also review studies on the role of normalization of [Ca2+]i in these abnormalities. Small but well-documented studies suggest that treatment of dialysis patients with calcium channels blockers can reverse the elevation of [Ca2+]i in B cells, which was followed by improvement of B-cell function. Thus, therapy with calcium channel blockers has the potential to decrease the infectious complication of uremia

Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone

Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone. Polymorphonuclear leukocytes (PMNLs) from uremic patients have elevated basal levels of cytosolic calcium ([Ca2+]i), reduced calcium signal after activation of Fcγ RIII receptor, and impaired phagocytosis. Chronic excess of parathyroid hormone (PTH) in uremia mediates its effect on PMNL's metabolism and function through the sustained elevation of their [Ca2+]i. Because calcium channel blockers interfere with this effect of PTH on PMNLs, treatment of patients on hemodialysis with verapamil, nifedipine, or amlodipine was associated with an improvement in metabolism and phagocytosis of PMNLs in humans. The therapy with calcium channel blockers should be continued in order to maintain its beneficial effects

Sexual dysfunction in the male patient with uremia: A reappraisal

Sexual dysfunction in the male patient with uremia: A reappraisal. Partial or complete impotence is common in uremia. It is not clear whether the impotence is organic or psychogenic in nature and whether uremia itself or the state of chronic illness is responsible for it. We examined these questions, by psychiatric interviews and nocturnal penile tumescence (NPT), in 50 normal subjects, 48 patients with chronic uremia, including 23 patients treated with maintenance dialysis, and 22 patients with chronic illness and normal renal function. About 40 to 50% of patients with uremia, but not those with chronic illness and normal renal function, complained of erectile dysfunction and reported a significant decrease in frequency of intercourse. There were no significant differences between patients with uremia prior to initiation of therapy and those treated with maintenance hemodialysis. NPT declines after 40 years of age. In all age groups, NPT was significantly (P < 0.01) lower in uremics than in normals or those with chronic illness. There was no correlation between erectile complaints, frequency of intercourse or NPT, and the presence or absence of depression. The frequency of intercourse correlated significantly (r = 0.68, P < 0.01) with NPT in patients with uremia. Data indicate that 50% of male patients with uremia have partial or complete impotence, which is most probably organic in nature and is related to uremia or its metabolic or hormonal consequences rather than to the state of chronic illness.Disfonctionnement sexuel chez le malade urémique de sexe masculin: Une réévaluation. L'impuissance partielle ou totale est fréquente au cours de l'urémie. La nature organique ou psychogénique de l'impuissance n'est pas claire et il n'est pas non plus établi si l'urémie par elle même ou la maladie chronique en sont responsables. Nous avons étudié ces prodromes chez 50 sujets normaux, 48 malades atteints d'urémie chronique, parmi lesquels 23 étaient traités par hémodialyse itérative., et 22 malades atteints d'affections chroniques, mais avec des fonctions rénales normales au moyen des interrogatoires psychiatriques et des érections nocturnes. Quarante à cinquante pour cent des malades urémiques, mais non pas ceux atteints de maladies chroniques avec des fonctions rénales normales, se sont plaint d'anomalies de l'érection et d'une diminution significative de la fréquence des rapports sexuels. Il n'a pas été observé de différence significative entre les malades urémiques non traitées et ceux soumis à l'hémodialyse. Les érections nocturnes dominent à partir de 40 ans. Dans tous les groupes d'age les érections nocturnes sont significativement (P < 0,01) moins fréquentes chez les urémiques que chez les sujets normaux ou les sujets atteints d'autres maladies chroniques. Il n'a pas été observé de corrélation entre la fréquence des rapports sexuels ou les érections nocturnes et la présence ou l'absence de dépression. La fréquence des rapports est significativement corrélée (r = 0,68; P < 0,01) à celle des érections nocturnes chez les sujets urémiques. Les résultats indiquent que 50% des malades urémiques males ont une impuissance partielle ou totale qui est très probablement d'origine organique et liée à l'urémie ou à ses conséquences métaboliques ou hormonales plutôt qu'à l'état de maladie chronique

Decreased O2 consumption by PMNL from humans and rats with CRF: Role of secondary hyperparathyroidism

Decreased O2 consumption by PMNL from humans and rats with CRF: Role of secondary hyperparathyroidism. Bactericidal ability of polymorphonuclear leukocytes (PMNL) is impaired in chronic renal failure (CRF). This function of PMNL is mediated by the generation of oxidizing radicals and the latter event requires O2 consumption by these cells. The present study examined both basal and FMLP-stimulated rise in cytosolic calcium ([Ca2+]i) and O2 consumption of PMNL from normal subjects and hemodialysis patients and from CRF rats, and evaluated the potential role of secondary hyperparathyroidism of CRF on these properties of PMNL. Basal levels of [Ca2+]i were significantly higher, and FMLP-induced increments in [Ca2+]i were significantly lower in PMNL of both humans and rats with CRF than in normals. Basal and FMLP-stimulated O2 consumption were significantly lower in CRF subjects and rats than in normals. These derangements were prevented by prior parathyroidectomy of CRF rats or by their treatment with verapamil from day one of CRF. Also, therapy of rats with pre-existing CRF with this drug reversed the abnormalities in [Ca2+]i and in O2 consumption of PMNL. The data indicate that: (1) CRF is associated with derangements in the homeostasis of [Ca2+]i of PMNL and their oxygen consumption, (2) these abnormalities are, most likely, mediated by the state of secondary hyperparathyroidism of CRF, and (3) verapamil, which blocks the PTH-induced entry of calcium into cells, and prevents as well as reverses these PMNL dysfunctions. These results implicate the excess PTH of CRF in the genesis of the defective bactericidal function of PMNL, and assign a new dimension to PTH toxicity in CRF

Insulin release from pancreatic islets: Effects of CRF and excess PTH

Insulin release from pancreatic islets: Effects of CRF and excess PTH. Insulin secretion may be impaired in chronic renal failure (CRF) and available data suggest that this abnormality may be related to the state of secondary hyperparathyroidism of renal failure. We directly measured insulin release from isolated islets of Langerhans obtained from normal rats, CRF-control and CRF-PTX (parathyroidectomized) rats, and parathyroid hormone (PTH)-treated animals. Both early and total glucose-induced insulin release from islets of CRF-control were markedly and significantly (P < 0.01) lower than from islets of normal rats. Insulin release from islets of CRF-PTX rats was significantly (P < 0.01) higher than that from islets of CRF-control rats, and not different from insulin release from islets of normal rats. Forskolin and IBMX, which cause a rise in cAMP, significantly stimulated glucose-induced insulin release from islets of normal, CRF-control and CRF-PTX rats, but the increments from baseline were not significantly different between the three groups. Both early and total insulin release from islets obtained from PTH-treated rats with normal renal function were markedly and significantly (P < 0.01) lower than values obtained from normal rats. Calcium contents of the pancreas of CRF-control and PTH-treated rats were significantly (P < 0.01) higher than that in pancreas of normal rats and CRF-PTX animals, and values in the latter two groups of animals were not significantly different. The results show that: 1) CRF impairs insulin release from pancreatic islets; 2) this abnormality is reversed by prior parathyroidectomy; and 3) hyperparathyroidism induced by PTH-treatment in normal rats impairs insulin release from pancreatic islets. The data provide a direct evidence for the role of secondary hyperparathyroidism in the genesis of abnormal carbohydrate metabolism in CRF. This effect of excess PTH is not related to alterations in cAMP production but may potentially be due to calcium accumulation in the pancreas

The duodenal mucosa in patients with renal failure: Response to 1,25(OH)2D3

The duodenal mucosa in patients with renal failure: Response to 1,25(OH)2D3. The structure of the duodenal mucosa was evaluated i n duodenal biopsy samples obtained from patients with moderate renal failure (MRF) and in dialysis patients (HD) in an effort to examine the possibility that changes in duodenal mucosa may contribute to the impaired calcium absorption in renal failure (RF). The effect of therapy with 1,25(OH)2D3 on the duodenal mucosa in the HD patients was also studied. The results show that both MRF and HD patients have reduction in calcium reabsorption and in the length of their intestinal villi and crypts of Lieberkuhn. In the HD patients, these structural changes were more severe. Treatment with 1,25(OH)2D3 produced significant improvement in calcium reabsorption (P < 0.01) as well as in length of villus and crypt (P < 0.02) and increased mitotic activity in the crypts (P < 0.02). Electron microscopy revealed the microvilli to be shorter, irregularly distributed, moth-eaten, and grainy, with these abnormalities disappearing after treatment. The data show that duodenal mucosa in RF exhibits structural abnormalities, which were normalized after 1,25(OH)2D3 therapy, and suggest that these derangements may play a role in the defective calcium reabsorption in RF.La muqueuse duodénale chez les malades en insuffisance rénale: Réponse au 1,25(OH)2D3. La structure de la muqueuse duodénale a été évaluée sur des biopsies duodénales de malades atteints d'insuffisance rénale modérée (MFR) et de malades en hémodialyse (HD) afin d'étudier l'hypothèse selon laquelle des modifications de la muqueuse duodénale pourraient contribuer à l'altération de l'absorption du calcium au cours de l'insuffisance rénale. L'effet du traitement par 1,25(OH)2D3 sur la muqueuse duodénale a été étudié chez les malades HD. Les résultats montrent que les malades MRF et HD ont une diminution de l'absorption du calcium et de la longueur de leurs villosités intestinales et de leurs cryptes de Lieberkuhn. Chez les malades HD ces modifications de structure sont encore plus sévères. Le traitement par 1,25(OH)2D3 détermine une amélioration significative de l'absorption du calcium (P < 0,01) de même qu'une augmentation de la longueur des villosités et des cryptes (P < 0,02) et une augmentation de l'activité mitotique dans les cryptes (P < 0,02). La microscopie électronique montre que les micro-villosités sont raccourcies, irrégulièrement distribuées et d'aspect mité et granuleux, anomalies qui disparaissent après le traitement. Les résultats montrent que la muqueuse duodénale des malades RF a des anomalies de structure qui sont normalisées au cours du traitement par 1,25(OH)2D3 et suggèrent que ces modifications peuvent jouer un rôle dans le déficit de au cours de RF

Elevation of cytosolic calcium of rat cardiac myocytes in phosphate depletion

Elevation of cytosolic calcium of rat cardiac myocytes in phosphate depletion. Phosphate depletion is associated with a rise in cytosolic calcium ([Ca2+]i) of cells and such a derangement is responsible in major part for organ dysfunction in phosphate depletion (PD). Cardiac function is impaired in PD, and it is possible that PD is also associated with rise in [Ca2+]i of cardiac myocytes. The present study examined the effect of PD on [Ca2+]i of cardiac myocytes and explored the mechanisms that may lead to the rise in their [Ca2+]i. The [Ca2+]i of cardiac myocytes began to rise and ATP content began to fall at the third week of PD. After six weeks of PD, the values of [Ca2+]i were significantly higher (P < 0.01) and those of ATP content were significantly lower (P < 0.01) than in control (PW) rats. The Vmax of Ca2+-ATPase and Na+,K+-ATPase as well as the Na+-Ca2+ exchange were significantly lower (P < 0.01) in PD than in PW animals. The data of the present study are consistent with the notion that the rise in [Ca2+]i of cardiac myocytes of PD rats is due to a decrease in calcium efflux out of them

Impaired insulin secretion of aging: Role of renal failure and hyperparathyroidism

Impaired insulin secretion of aging: Role of renal failure and hyperparathyroidism. Available data indicate that insulin secretion is impaired with aging. Almost all the studies that examined insulin secretion by old animals did not take into consideration the state of renal function or the blood levels of parathyroid hormone (PTH). Old animals may have chronic renal failure (CRF) and secondary hyperparathyroidism, and both of these conditions impair insulin secretion. It is possible, therefore, that the impaired insulin secretion of aging is not due to old age per se, but rather to associated CRF and excess PTH. The present study examined this issue in adult (6 month old) and senescent rats (2 years old) with and without CRF and excess PTH. Senescent rats without CRF had normal renal function and normal blood levels of PTH, and the values were not different from those observed in adult rats. Creatinine clearance in senescent rats with CRF was significantly (P < 0.01) lower and serum levels of PTH were significantly (P < 0.01) higher than in senescent animals without CRF and than in the adult rats as well. Only the senescent rats with CRF displayed glucose intolerance during intravenous glucose tolerance test. For any given level of blood glucose, plasma insulin levels were lower in senescent rats with CRF than in the adult rat or senescent animals without CRF. Both initial phase (139 ± 45 pg/islet · 8 min) and total (808 ± 216 pg/islet · 33 min) insulin secretion from pancreatic islets of the senescent rats with CRF and excess PTH were significantly lower than those in senescent rats with normal renal function (658 ± 117 pg/islet · 8 min and 3294 ± 290 pg/islet · 33 min, respectively) or in adult rats (710 ± 134 pg/islet · 8 min and 3183 ± 366 pg/islet · 33 min, respectively). There were no significant differences in insulin secretion between the adult rats and the senescent ones with normal renal function. The data demonstrate that the impaired insulin secretion by the pancreatic islets in old rats is not necessarily related to the higher age per se, but is due to the associated CRF and secondary hyperparathyroidism that develops in many, but not all old animals. Our results indicate that studies examining the effect of aging on body function should take into consideration the level of renal function and of the serum PTH, since both CRF and excess PTH adversely affect the functional integrity of many organs

Inhibition of immunoglobulin production by parathyroid hormone. Implications in chronic renal failure

Inhibition of immunoglobulin production by parathyroid hormone. Implications in chronic renal failure. Available data indicate that B cell proliferation is inhibited in chronic renal failure and this is due to excess blood levels of PTH. This defect may also affect immunoglobulin production. We examined production of IgG, IgM and IgA by B cells stimulated with Staphylococcus aureus Cowan I (SAC) or with pokeweed mitogen (PWM) after eight days of culture and evaluated the effect of PTH on this process in 34 hemodialysis patients and 44 normal subjects. IgG, IgM and IgA production by B cells from patients was lower (P < 0.01) than by B cells from normal subjects. Both 1-34 and 1-84 PTH inhibited (P < 0.01) immunoglobulin production by B cells from normal subjects and dialysis patients. However, this inhibitory effect was evident in dialysis patients only with the higher dose of PTH. The inhibition of immunoglobulin production by PTH occurred only when the hormone was added at the initiation of the B cell culture. Inactivation of PTH abolished its inhibitory effect on immunoglobulin production. Agents that stimulate cAMP production (forskolin, cholera toxin) and the cAMP analogue, 8-bromoadenosine 3′,5′ cyclic monophosphate inhibited immunoglobulin production by B cells from both normal and dialysis patients, and the degree of inhibition was not different between the two groups. The calcium inophore A23187 also inhibited IgG, IgA and IgM production by B cells from normal subjects and dialysis patients; there was no significant difference in the degree of inhibition between the two groups. The resting levels of cytosolic calcium in B cells of dialysis patients was significantly (P < 0.01) higher than that of B cells from normal subjects. The data show that: (1) immunoglobulin production is impaired in dialysis patients; (2) B cells of dialysis patients have elevated resting levels of cytosolic calcium; (3) PTH inhibits IgG, IgA and IgM production and this effect is at least partly mediated by PTH-induced cAMP production and alterations in cytosolic calcium into B cells; (4) this inhibitory effect is mediated by events that affect initial stages of B cell proliferation and maturation; (5) the requirement for high dose of PTH for its inhibitory effect on B cells from dialysis patients is probably due to desensitization and/or down-regulation of PTH receptors on B cells. The results are consistent with the proposition that impaired immunoglobulin production by B cells from dialysis patients is at least partly due to the state of secondary hyperparathyroidism in these patients