Search

Nutritional zinc deficiency induces thymic atrophy, but the underlying mechanisms remain unknown. In this study, we investigated the mechanism of thymic atrophy and fatty degeneration associated with zinc deficiency and its effect on T cell maturation. Building on previous research demonstrating the beneficial effect of IL-4 administration or zinc supplementation on the spleen in zinc-deficient rats, we further examined whether these supplements also improve thymic atrophy. Five-week-old male Sprague-Dawley rats were fed a standard diet, zinc-deficient diet (n = 16 each) with either saline or IL-4, or a zinc-deficient diet for 6 weeks followed by a standard diet for 4 weeks. Relative thymus weights, serum thymulin concentrations, and the number of cytokeratin-8-positive cells, AIRE-positive cells, IL-7-positive cells, CD8 + T cells, CD4 + T cells, pre-T cells, and CD25 + CD44 + (DN3) cells in the thymus of zinc-deficient rats significantly decreased compared with those in all other groups. Conversely, PPAR-γ-positive cells, oil red O-positive areas, pro T cells, CD25 - CD44 + cells, TUNEL-positive cells, Viobility 405/452 Fixable Dye-positive cells, CD68-, CD163- or CD169- macrophages, and IL-1β concentrations were significantly increased in the thymus of zinc-deficient rats as compared to those in the other groups. After IL-4 administration or zinc supplementation for zinc deficiency, all the measurement indices were recovered to levels in standard rats. It was demonstrated that zinc deficiency caused thymic atrophy, accompanied by fatty degeneration in the cortical regions and affected T cell maturation. IL-4 administration or zinc supplementation for zinc deficiency ameliorated thymic fatty degeneration., (© 2022 John Wiley & Sons Ltd.)

Nutritional zinc deficiency aggravates inflammation, subsequently causing anemia and splenomegaly in rats; however, the mechanism underlying such splenomegaly remains poorly understood. Therefore, in this study, we aimed to elucidate the mechanisms underlying the splenomegaly and anemia occurring in zinc-deficient rats and investigate whether these effects of zinc deficiency could be reversed by interleukin (IL)-4 administration or zinc supplementation. Five-week-old male Sprague-Dawley rats were fed a standard diet; fed a zinc-deficient diet (n = 7 each) and injected with saline or IL-4; or fed a zinc-deficient diet for 6 weeks followed by a standard diet for 4 weeks thereafter. White blood cells, segmented neutrophils, platelets, CD4 + T cells, CD11b/c + granulocytes, CINC/GRO + cells, and myeloperoxidase-positive cells in the blood and spleen of the zinc-deficient rats were significantly higher than those in all the other groups. Conversely, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, lymphocytes, and CD8 + T cells in the blood of the zinc-deficient rats were significantly lower than those in the other groups. Furthermore, serum aspartate aminotransferase, lactate dehydrogenase, indirect bilirubin concentrations, and erythrocyte osmotic fragility in the zinc-deficient rats were significantly higher than those in the other groups. Moreover, zinc deficiency significantly decreased the GATA1 protein levels in the spleen. Collectively, these results indicate that zinc deficiency aggravates the inflammatory response and causes hemolytic anemia and splenomegaly. Importantly, IL-4 administration and zinc supplementation can reverse the zinc deficiency-induced hemolytic anemia and splenomegaly.

Background: Zinc plays an important role in appetite regulation. L-Carnosine, an endogenous dipeptide, may also regulate eating behavior via its histaminergic and antiglutamatergic properties. Polaprezinc (zinc-L-carnosine complex) is a medication for gastric ulcers. A small case series reported successful treatment of binge eating with add-on polaprezinc., Methods: This was an open trial of add-on polaprezinc in patients with binge eating disorder (BED; n = 22) or bulimia nervosa (BN; n = 7) receiving antidepressants. A 4-week baseline period was followed by a 16-week polaprezinc treatment at 150 mg/d (containing 34 mg zinc and 116 mg L-carnosine) in addition to ongoing psychotropic medications. We also assessed their zinc status via a laboratory index and zinc deficiency-related symptoms., Results: At the study end, both conditions showed a significant reduction in the 4-week frequency of combined objective and subjective binge eating episodes, the 4-week frequency of days when at least 1 such episode occurred (only in BED), several aspects of eating disorder psychopathology (rated by the Eating Disorder Examination-Questionnaire), and comorbid depressive symptoms (rated by the 16-item Quick Inventory of Depressive Symptomatology [Self-Report]). Serum copper/zinc ratio decreased from 1.4 to 1.1 on average in both conditions. All patients had multiple zinc deficiency-related symptoms at baseline that substantially improved after polaprezinc treatment. Overall, the effectiveness of polaprezinc was greater in BED patients than in BN patients, with minor adverse effects., Conclusions: These findings offer preliminary evidence for the effectiveness of polaprezinc in treating BED and BN and suggest the involvement of zinc deficiency in these conditions.

Nutritional zinc deficiency leads to immune dysfunction and aggravates inflammation. However, the underlying mechanism remains unknown. In this study, the relationship between macrophage subtypes (M1 and M2) and helper T lymphocytes (Th1 and Th2) was investigated using the spleen from rats fed zinc-deficient or standard diet. In experiment I, 5-week-old male Sprague-Dawley rats were fed a zinc-deficient diet (without zinc additives) or a standard diet (containing 0·01% zinc) for 6 weeks. In experiment II, the rats were divided into four groups: one group was fed a standard diet for 6 weeks; two groups were fed zinc-deficient diets and were injected three times a week with either saline or interleukin-4 (IL-4) (zinc-deficient/IL-4 i.p.); a fourth group (zinc-deficient/standard) was fed a zinc-deficient diet for 6 weeks followed by a standard diet for 4 weeks. In experiment I; GATA-binding protein 3 (GATA-3) protein level, M2 macrophage, CD3 +  CD8 + cells, and IL-4/IL-13-positive cells significantly decreased in the spleens of the zinc-deficient group. Additionally, IL-1β and macrophage inflammatory protein-1α (MIP-1α) mRNA levels significantly increased in the splenic macrophages of the zinc-deficient group. In experiment II; M2 macrophages, CD3 +  CD8 + cells, IL-4/IL-13-positive cells, and GATA-3 protein levels significantly increased in the spleens of the zinc-deficient/IL-4 i.p. and zinc-deficient/standard groups. Furthermore, IL-1β and MIP-1α mRNA levels decreased in the splenic macrophages of the zinc-deficient/IL-4 i.p. and zinc-deficient/standard groups. Zinc deficiency-induced aggravated inflammation is related to Th2 lymphocytes and followed by the association with loss of GATA-3, IL-4 and anti-inflammatory M2 macrophages. Importantly, IL-4 injection or zinc supplementation can reverse the effects of zinc deficiency on immune function., (© 2018 John Wiley & Sons Ltd.)

Although zinc (Zn) deficiency is often suspected in patients with taste disorders, it may be difficult to diagnose Zn deficiency, especially in patients without any clear risk factors. Accordingly, the aim of the present study was to detect possible markers for taste disorders or zinc deficiency. To achieve this aim, we analyzed data obtained from 122 Japanese men who were not using medicines and had no diseases requiring treatment. We evaluated the following factors: awareness of dysgeusia; salty taste recognition threshold (SRT); the serum concentrations of Zn, copper (Cu), iron, alkaline phosphatase, and albumin; and the Cu/Zn ratio. The serum Cu/Zn ratio was positively correlated with the both the SRT and the awareness of dysgeusia. The serum Zn concentration was not correlated with the SRT or the awareness of dysgeusia in univariate analyses. However, in multivariate logistic regression, the serum Zn concentration was associated with the awareness of dysgeusia. In conclusion, the serum Cu/Zn ratio is a good diagnostic marker for taste disorders and the value of 1.1 may be a threshold level for detecting taste disorders., (Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.)

We investigated whether or not an intervention of providing food information improves serum Zn levels in ninety-two 18-20-year-old Japanese women. The mean serum Zn level of the participants was 73.09 ± 10.56 (mean ± SD) μg/dL, where 79 % of the participants had lower than the reference Zn level (80 μg/dL) proposed by the Japan Society for Biomedical Research on Trace Elements. Participants were divided into food information (INF) group, supplement (SPL) group, and control (C) group, and their serum Zn levels were measured before and after 2 weeks of intervention. The results showed that changes in serum Zn levels were (expressed in μg/dL): 71.23 ± 8.42 to 76.83 ± 12.22 in INF group (NS; not significant), 72.72 ± 10.77 to 84.07 ± 12.03 in SPL group (P < 0.01), and 72.69 ± 9.46 to 74.52 ± 11.44 in C group (NS). Percentage of normal subjects in serum Zn level (>79 mg/dL) were significantly increased in INF group (16.7 to 40%, P < 0.05) and SPL group (17.2 to 69%, P < 0.001) by each intervention. Food information only entailed a table of food items with high Zn content (card-type) and Zn intake menu (recipes). The results suggested that providing food information is effective in improving latent low Zn in young Japanese women.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, N ω -nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO - ) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO - Indeed, the activity of the endogenous OO - scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO - generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^{., (© The Author(s) 2014.)}

The aim of the present study was to examine whether zinc (Zn) deficiency augmented the frequency of micronuclei, an indicator of chromosome aberration, and the induction of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of cellular DNA damage derived from oxidative stress, in rat bone marrow cells or not. Both the frequency of micronuclei and the induction of 8-OHdG were significantly increased in rats fed with a Zn-deficient versus a standard diet for 6 weeks (p < 0.005). The supplementation of Zn with a standard diet for 4 weeks to rats fed with a Zn-deficient diet for 6 weeks restored the enhanced induction of micronuclei and 8-OHdG to levels comparable to those seen in rats fed with a standard diet for 10 weeks, indicating that the shortage of Zn in the body is involved in the induction of micronuclei and 8-OHdG. Again, the membrane-permeable superoxide dismutase mimetic superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, treatment (100 μmol/kg, twice a day) for 10 days prior to the termination of dietary treatment reduced the induction of micronuclei and 8-OHdG in rats fed with a Zn-deficient diet for 6 weeks to levels comparable to those in rats fed with a standard diet for 6 weeks, indicating that superoxide radical participates in the induction of micronuclei and 8-OHdG. In fact, the endogenous superoxide scavenger, Cu/Zn superoxide dismutase, was significantly reduced in the bone marrow cells of rats fed with a Zn-deficient diet for 6 weeks when compared to those of rats fed with a standard diet for 6 weeks (p < 0.005). These observations demonstrate that Zn deficiency elevates the frequency of micronuclei and the induction of 8-OHdG through an increase in the biological action of the superoxide radical. This suggests an increase in carcinogenic initiation resulting from Zn deficiency-induced oxidative stress.

This study investigated the effects of excess zinc intake on the mean arterial pressure (MAP), renal blood flow (RBF), inulin clearance (IC), serum zinc level, serum angiotensin-converting enzyme (ACE) activity, and kidney angiotensin II (AT II) levels in rats. Experiments were performed on male Sprague-Dawley rats maintained for 4 weeks on a diet containing either 5 mg/100 g (control group), 50 mg/100 g (Zn50 group), or 200 mg/100 g (Zn200 group) zinc carbonate. Serum zinc levels significantly increased to 126.5 % in the Zn50 group and 198.1 % in the Zn200 group compared with controls. MAP significantly increased to 107.8 % in the Zn50 group and 114.5 % in the Zn200 group again compared with controls. Although the difference in serum ACE activity was independent of the serum zinc levels, the kidney AT II levels increased significantly to 137.2 % in the Zn50 group and 174.4 % in the Zn200 group compared with the controls. RBF was decreased significantly to 74.4 % in the Zn50 group and 69.7 % in the Zn200 group compared with the controls. IC values were significantly decreased to 69.6 % in the Zn50 group and 52.7 % in the Zn200 group as compared with control levels. Combined together, these results show that excessive Zn intake reduced IC and RBF and increased MAP and kidney AT II levels, suggesting that excessive Zn intake reduces renal function.

To elucidate the pathophysiology of zinc (Zn)-induced iron (Fe) deficiency anemia (IDA), we examined hemoglobin (Hb) concentrations, hematocrit (Ht) levels, numbers of circulating red blood cells (RBC) and reticulocytes, values of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC), serum Zn, Fe and erythropoietin (EPO) concentrations and histopathological changes in the bone marrow, spleen and liver using rats fed with a standard or high Zn diet for 20 weeks. Rats fed with the high Zn diet exhibited a significant decrease in Hb concentrations, Ht levels and MCV, MCH and MCHC values, indicating microcytic hypochromic anemia characterized by Fe deficiency. Also, a marked decrease in serum Fe concentrations was seen in rats fed with the high Zn diet relative to rats fed with the standard diet. Interestingly, the number of RBC was comparable in both groups of rats, although a decrease in the number of RBC is ordinarily seen in IDA. There were reticulocytosis and extra-medullary erythropoiesis in the spleen and an increase in serum EPO concentrations in rats fed with the high Zn diet vs. those on the standard diet. These observations suggest that both reticulocytosis and extra-medullary erythropoiesis in the spleen played a role in maintaining the number of RBC in rats fed with the high Zn diet, preventing further progression of anemia. Further, increased production of EPO may be involved in the induction of reticulocytosis and extra-medullary erythropoiesis in the spleen.

Zinc is an essential trace element and serves as the active center of approximately 300 enzymes. Therefore, zinc deficiency may be associated with a variety of clinical features such as hypogeusia, hyposmia, growth retardation, dermatitis, alopecia, gonadal hypofunction, abnormal pregnancy, susceptibility to infections, delayed wound healing, impaired glucose tolerance, and increased carcinogenesis. Zinc deficiency was reported to be on the increase in the Nagano Study conducted from 2003 to 2005. Zinc therapy is classified into two categories, zinc-supplementary and -specific treatments. Ordinarily, zinc-supplementary therapy is carried out for the symptoms and diseases caused by zinc deficiency. On the other hand, zinc-specific therapy is applied to obtain copper- and iron-chelating, antifibrotic, and antidiabetic effects. The availability of zinc-specific therapy is now confirmed in humans and animals. Hereafter, the safety of zinc therapy needs to be examined further.

Objectives: The present study was designed to examine whether or not excessive Zn intake affects systemic blood pressure (BP) levels in a normotensive state., Methods: Systolic BP (SBP) and mean arterial pressure (MAP) before and after administration of the nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME) or the exogenous superoxide scavenger, tempol and the activity of the endogenous superoxide scavenger, Cu/Zn-superoxide dismutase (SOD) and levels of endothelial type (e)NOS mRNA and protein in the thoracic aorta were analyzed in male Sprague-Dawley rats fed a standard diet containing 0.005% Zn or a high Zn diet containing 0.5% Zn for 8 weeks., Results: SBP and MAP levels observed at the end of dietary conditioning were significantly elevated in rats fed a high Zn diet relative to rats fed a standard diet. Administration of L-NAME caused an increase in MAP levels in rats fed a standard and a high Zn diet, demonstrating the involvement of the vasodilator, nitric oxide (NO) in the regulation of systemic BP in the two groups of rats. However, the expression of eNOS mRNA and protein in the thoracic aorta was not significantly different between rats fed a standard and a high Zn diet. On the other hand, administration of tempol led to a decrease in MAP levels in rats fed a standard and a high Zn diet, indicating the participation of the oxygen free radical, superoxide in the modification of systemic BP in the two groups of rats. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO through the formation of peroxynitrite based on the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment dramatically restored MAP levels in rats fed a high Zn diet to levels comparable with those observed in rats fed a standard diet, indicating that an elevation in systemic BP levels seen in rats fed a high Zn versus a standard diet is presumably brought by a reduction in the action of the vasodilator, NO resulting from an increase in the action of superoxide. The activity of Cu/Zn-SOD in the thoracic aorta was significantly reduced in rats fed a high Zn diet relative to rats fed a standard diet, appearing to at least in part, play a role in an increase in the action of superoxide in the vessel wall of rats fed a high Zn diet., Conclusions: Excessive Zn intake may be a factor to elevate systemic BP levels in a normotensive state presumably through the oxidative stress caused by superoxide.

Because zinc (Zn) is an important component for cell protection against certain oxygen species, it has been suggested that Zn deficiency impairs the potent oxidant defense capacity, which is constitutively provided in the vascular system. However, the influence of dietary Zn deficiency on systemic blood pressure and vascular system is controversial and unclear. We therefore examine the effect of dietary Zn deficiency on systemic blood pressure, a potent superoxide scavenger, aortic Cu/Zn superoxide dismutase (SOD) activity, a most representative synthase of the endothelium-derived relaxing factor, and aortic endothelial nitric oxide synthase (eNOS) expression. Furthermore, the direct effects of intravenous administration of NOS inhibitor, Nomega-nitro-L-arginine methyl ester (LNAME), and a SOD mimetic compound, tempol, in normotensives were tested in Wistar-Kyoto (WKY) rats. A Zn-deficient diet (4 wk) contributed to growth retardation, the decrease in thymus weight, and the lower levels of serum Zn compared with the standard diet group. However, no significant difference in conscious systolic and diastolic blood pressure was found in the Zn-deficiency group. The administration of L-NAME caused an increase in the mean arterial pressure (MAP) levels in the two groups of rats and the involvement of the vasodilator nitric oxide (NO) in the regulation of systemic BP in the normotensive state. On the other hand, administration of the superoxide scavenger, tempol, led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in the maintenance of the systemic BP in a normotensive state. There were no significant differences between the Zn-deficient diet group and the standard diet group in the normotensive state. eNOS expression and Cu/Zn SOD activity in the aorta were also intact in Zn-deficient normotensive rats. These findings suggest that the 4 wk of Zn deficiency was inadequate to alter systemic blood pressure and focal NO signaling in the normotensive state. Long-term Zn deficiency affects the neuronal, immune, and hematopoietic systems, which contribute to systemic and/or local circulation. However, Zn deficiency alone does not cause hypertension and local vascular dysfunction in the normotensive state.

1. Zinc deficiency (ZD) induces many kinds of pathological states. However, the effects of ZD on haemodynamics remain unclear. In the present study, we measured mean blood pressure (BP) and renal blood flow (RBF) under anaesthesia and calculated renal vascular resistance (RVR) from these parameters in rats maintained on a ZD diet (0.5 p.p.m. zinc) for 4 weeks. 2. Zinc deficiency did not change mean BP, but significantly reduced RBF and increased RVR (each P < 0.01). In addition, these effects of ZD were reversible. 3. Because Cu/Zn superoxide dismutase (SOD) is a zinc-containing enzyme and superoxide is a potent scavenger of nitric oxide (NO), a vasodilator, we hypothesized that one of the mechanisms by which ZD increases RVR is by decreasing NO bioavailability by the enhanced formation of superoxide due to low Cu/Zn SOD activity. To test this hypothesis, we observed the roles of NO and superoxide in the mechanism, after having confirmed the low activity of Cu/Zn SOD in the kidneys of ZD rats. 4. Administration of the SOD mimetic tempol (5 mg/kg per min) decreased RVR to a significantly greater extent in ZD rats compared with control, suggesting that superoxide was responsible for the mechanism. Low doses of the NO donor sodium nitroprusside (SNP; 2.0 micro g/kg per min, continuous) decreased RVR to a significantly smaller extent in ZD rats compared with control, whereas a high dose of SNP (0.75 mg/kg, bolus) decreased RVR to a significantly greater extent in ZD rats compared with control, suggesting that the mechanism includes an inhibition of NO activity in ZD, which is most likely to be a scavenging of NO by the activated superoxide. 5. In summary, ZD may increase RVR. The mechanism probably includes changes in NO and superoxide activities.

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet > SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.

Zinc deficient rats were prepared to investigate histopathological changes in thymus, testis, skin, esophagus, kidney and liver and the relationship between these changes and apoptosis. Seven-week-old male SD rats were given a Zn deficient diet (0% Zn diet) or a standard diet (0.02% Zn diet). The above-mentioned organs were excised 1, 2, 3, 4, 5, 10, 13, and 34 weeks after initiating diet administration. Then, these organs were examined morphologically, and apoptotic changes were analyzed by either the TdT- mediated dUTP - biotin nick end labeling (TUNEL) or electrophoresis. Significant morphological changes were seen only in rats on the 0% Zn diet. After 4 weeks, atrophy of the thymus was seen. After 5 weeks, oligospemia was observed, and after 10 weeks, testicular atrophy accompanied by the loss of sperm cells and spermatocytes was confirmed. In addition, after 10 weeks, thickening of epithelia was seen in the skin and esophagus of rats on the 0% diet. During the observation period, no marked morphological changes were observed in the liver or kidney. In the thymus and testis of rats on the 0% Zn diet, prior to detecting any morphological changes, increases in apoptosis were confirmed at 1 and 3 weeks after initiating diet administration, respectively. In the kidney and liver, TUNEL positive cells appeared after 13 and 34 weeks, respectively. These observations suggest that the functional and morphological changes in the thymus and testis of rats on the 0% Zn diet are caused by increased apoptosis, and that even when the supply of Zn is terminated for only a short period of time, immunocytes and germ cells can not survive or regenerate sufficiently. Again, the fact that even in the liver and kidney, apoptosis was observed when administration of the 0% Zn diet was prolonged suggests that the appearance of apoptosis is dependent on the amount of Zn in tissues. In addition, the fact that increases in apoptosis were confirmed in the skin of rats on the 0% Zn diet, but not in the esophagus of these rats suggests that apoptosis does not directly cause thickening of stratified squamous epithelium in Zn deficient rats.

Background: Zinc (Zn) is an essential trace element in humans and animals. We have recently documented that Zn deficiency may aggravate tubulointerstitial nephropathy seen in the obstructed kidney (OK) of 72 hours duration through a further increase in the activity of endogenous angiotensin II in the OK. Also, it is known that the vasoconstrictors angiotensin II and endothelin (ET)-1 may be implicated in the deterioration of glomerular hemodynamics caused in the OK. We therefore designed the present study to examine the effect of Zn deficiency on the expression of ET-1 and a potential role of endogenous angiotensin II in the expression of ET-1 in glomeruli of the OK of 72 hours duration., Methods: Using reverse transcription-polymerase chain reaction and immunohistochemistry, the expression of prepro-ET-1 mRNA and ET-1 was examined in glomeruli of the contralateral, non-obstructed control kidney (CLK) and the OK from rats with unilateral ureteral obstruction (UUO) of 72 hours duration fed a standard or a Zn-deficient diet for approximately 50 days. The rats in each group were treated with saline alone or the angiotensin-converting enzyme inhibitor enalapril before and after ureteral obstruction., Results: The expression of prepro-ET-1 mRNA and ET-1 was markedly greater in the OK than in the CLK in the standard and the Zn-deficient diet groups. However, the expression of prepro-ET-1 mRNA and ET-1 was substantially increased in the OK of the Zn-deficient diet group relative to the OK of the standard diet group. There were no significant differences in the expression of prepro-ET-1 mRNA and ET-1 between the CLK of the two diet groups. Administration of enalapril restored the expression of prepro-ET-1 mRNA and ET-1 in the OK to levels seen in the CLK in the standard and the Zn-deficient diet groups. Enalapril produced no effects on the expression of prepro-ET-1 mRNA and ET-1 in the CLK of the two diet groups., Conclusions: UUO of 72 hours duration may increase the expression of prepro-ET-1 mRNA and ET-1 in glomeruli of the OK through an increment in the biological action of endogenous angiotensin II in the OK. Moreover, Zn deficiency may enhance the expression of prepro-ET-1 mRNA and ET-1 in glomeruli of the OK through a further increment in the biological action of endogenous angiotensin II in the OK. Zn deficiency appears to be a factor to worsen glomerular hemodynamics in the OK of the UUO setting of 72 hours duration through an increment in the biological action of the vasoconstrictors angiotensin II and ET-1.

Ureteral ligation causes tubulointerstitial nephropathy characterized by the tubular dilatation, the interstitial expansion, and a leukocyte infiltration into the tubulointerstitium. The present study was designed to explore whether zinc (Zn) deficiency affects the development of unilateral ureteral obstruction (UUO)-induced tubulointerstitial nephropathy. Compared to rats fed a standard diet, rats fed a Zn-deficient diet exhibited a greater influx of leukocytes into the tubulointerstitium of the cortex of the obstructed kidney 3 d following UUO. Furthermore, rats fed a Zn-deficient diet showed a slight invasion of leukocytes into the tubulointerstitium of the cortex of the contralateral nonobstructed kidney (CLK), although there was no infiltration of leukocytes into the CLK of rats fed a standard diet. These histological changes, however, were ameliorated by administration of enalapril, an angiotensin (ANG) I-converting enzyme inhibitor. Thus, it is suggested that Zn deficiency aggravates UUO-induced tubulointerstitial nephropathy via an increase in the action of ANG II.