Takanobu Sakemi

Estrogen Attenuates Progressive Glomerular Injury in Hypercholesterolemic Male Imai Rats

Hypercholesterolemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially in males. A sex difference in glomerular injury has been recognized, but the role of sex hormones in glomerular injury remains unclear. Therefore, we investigated whether estrogen administration influences the progressive glomerular injury in male Imai rats. Estrogen produced a significant decrease in body weight. Systolic blood pressure in estrogen-treated rats was significantly lower than that in controls. Estrogen attenuated the progression of glomerular injury by significantly reducing proteinuria and glomerular sclerosis. The glomerulosclerosis index was significantly higher in controls than in estrogen-treated rats. Estrogen suppressed serum testosterone levels, whereas it increased GH levels. Results suggest that estrogen appears to play an inhibitory role on the development of glomerular injury, by itself or in association with sex-related factors regulated by estrogen and testosterone.

Testosterone eliminates the attenuating effect of castration on the progressive glomerular injury in hypercholesterolemic male Imai rats.

Hypercholesterolemic Imai rats, especially males, spontaneously develop proteinuria and glomerulosclerosis. We have shown that castration attenuated the progression of glomerular injury in male Imai rats. The present study was designed to investigate whether the attenuating effect of castration on glomerulosclerosis is eliminated by administration of testosterone. Testosterone propionate (TP) eliminated the attenuating effect of castration on the progression of glomerular injury by significantly and dose dependently increasing proteinuria and enhancing glomerular sclerosis. TP at 1 mg failed to reverse glomerulosclerosis to the control levels, despite a dose of TP sufficient to restore urinary protein excretion, serom testosterone level and glomerular growth. The results indicated that besides testosterone other sex-related hormones may be involved in the development of glomerulosclerosis in male Imai rats.

Different Effects of Castration and Estrogen Administration on Glomerular Injury in Spontaneously Hyperglycemic Otsuka Long-Evans Tokushima Fatty (OLETF) Rats

Aim: Non-insulin-dependent diabetic mellitus model rats, Otsuka-Long-Evans-Tokushima-Fatty (OLETF), develop diabetic nephropathy presenting with mesangial expansion leading to glomerular sclerosis and thickening of the glomerular basement membrane (GBM), especially in elderly males. The effects of sex hormones and castration on the incidence of diabetes mellitus (DM) have been studied in this strain rat. However, there have been no detailed studies on the effects of castration and sex hormone in the development of diabetic nephropathy. Methods: In this study we examine the effect of castration or estrogen on the development of glomerular injury in OLETF rats. Thirty male OLETF rats and 10 male long-Evans Tokushima Otsuka (LETO) rats as a normal control were used. OLETF rats were divided into three groups: group 1 received sham-operation, group 2 was castrated at 6 weeks, and group 3 was administered 0.1 mg estrogen subcutaneously once a month from 6 weeks to 58 weeks of age and LETO rats were assigned to group 4. Body weight, urinary protein and fasting blood glucose, serum albumin and other serum constituents were investigated every 12 weeks from 12 weeks to 60 weeks of age. In groups 1–3, glucose tolerance test was performed at 38 weeks. Each group was studied morphologically at the end of the experiment (60 weeks of age). Results: Castration attenuated proteinuria and glomerular sclerosis accompanied by an amelioration of glucose tolerance, a decrease in mesangial expansion and an attenuation of the GBM thickening. In contrast, although estrogen equally ameliorated glucose tolerance and attenuated the mesangial expansion and the GBM thickening, estrogen failed to attenuate proteinuria and glomerulosclerosis. A significant increase in glomerular tuft volume, and serum levels of growth hormone, total cholesterol and triglycerides was observed in the estrogen-treated rats as compared with the castrated rats. Conclusion: Besides the mechanisms involved in the development of diabetic nephropathy, other mechanisms may be involved and contribute to the development of glomerulosclerosis in the estrogen-treated rats, leading to a difference in glomerular injury between the castrated and estrogen-treated OLETF rats.

Autopsy report of acute necrotizing opticomyelopathy associated with thyroid cancer

We report an autopsied case of paraneoplastic necrotizing myelopathy. The patient had bilateral blindness, quadriplegia, and dyspnea of acute onset and died without remission 7 weeks later. The severe tissue necrosis and demyelination were found in the optic chiasm and from the medulla oblongata throughout the whole length of spinal cord. A papillary carcinoma was found in the thyroid gland at autopsy. In the present case IgG, myelin basic protein and activated helper T cells were increased in the CSF at onset, suggesting a mechanism of autoimmune demyelination for the condition.

Sex difference in progression of adriamycin-induced nephropathy in rats

To clarify the pathogenesis of focal-segmental glomerulosclerosis, we investigated the sex-related difference and the effect of castration in Adriamycin (ADR) induced nephropathy of Sprague-Dawley rats. At 5 weeks of age, group 1 female and group 2 male rats were sham operated, and group 3 male rats were castrated. ADR 2 mg/kg was intravenously administered to all rats at 8 weeks of age twice at a 20-day interval. Body weight, blood pressure, urinary protein, and serum constituents were investigated every 4 weeks, 4-20 weeks after the second ADR injection. Each group was studied morphologically 12 and 20 weeks after the second ADR injection. ADR induced massive proteinuria in male rats, whereas it induced significantly lower proteinuria in female rats, and castration significantly reduced proteinuria of male rats to an extent equal to the levels seen in female rats. Control male rats had significantly lower serum albumin levels and a significantly greater impairment of renal function (blood urea nitrogen and creatinine levels) than the female rats or the castrated male rats at 20 weeks. The glomerulosclerosis index was significantly higher in control male rats than in female rats, and castration attenuated glomerular injury of male rats to an extent close to the levels seen in female rats, though there was a significant difference in the glomerulosclerosis index between female rats and castrated male rats. The three groups did not differ in blood pressure and plasma somatomedin C and serum growth hormone levels, whereas the plasma testosterone levels were decreased to undetectable in female and castrated male rats, resulting in a reduction of sex-related low molecular weight protein in urine. These observations suggest that sex hormones such as testosterone and estrogen and/or sex-related low molecular weight protein regulated by testosterone and estrogen may play a contributory role in sex differences in the progression of glomerulosclerosis in ADR-treated rats.

Castration Attenuates Proteinuria and Glomerular Injury in Hyperlipidemic Male Imai Rats

Hyperlipidemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially in males. We investigated the effect of castration on spontaneous proteinuria and progressive renal injury in male Imai ats. Male Imai rats (n = 16) were castrated at 5 weeks of age. Body weight, blood pressure, urinary protein excretion and serum constituents were checked and compared with sham-operated control rats (n = 16) up to 24 weeks. Sham-operated group 1 (n = 5) and castrated group 2 (n = 6) underwent morphological study after 16 weeks of observation and sham-operated group 3 (n = 11) and castrated group 4 (n = 10) were followed for an additional 8 weeks and used for morphological study. Growth rate was significantly stunted in castrated rats as compared with the controls. Castration significantly reduced proteinuria almost throughout the experiment (167 +/- 84 vs. 46 +/- 24 mg/kg/day, p < 0.001, at 8 weeks and 688 +/- 211 vs. 458 +/- 97, p < 0.01, at 20 weeks). The glomerulosclerosis index was significantly higher in sham-operated control rats than in castrated rats (28.8 +/- 18.0 vs. 7.3 +/- 3.1, p < 0.01, at 16 weeks, and 92.1 +/- 35.5 vs. 39.5 +/- 8.9, p < 0.001, at 24 weeks). There were no significant differences in blood pressure, serum cholesterol, plasma renin activity, plasma somatomedin C levels between the two groups. These results raise the possibility that sex hormones may partly contribute to spontaneous proteinuria and progressive renal injury in male Imai rats.

Angiotensin-Converting Enzyme Inhibition Attenuates Hypercholesterolemia and Glomerular Injury in Hyperlipidemic Imai Rats

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. We investigated the effect of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneous hypercholesterolemia and the progressive renal injury in this rat strain. Male Imai rats (n = 7) were treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Body weight, blood pressure, urinary protein excretion and serum constituents were checked and compared with untreated controls (n = 5) up to 38 weeks of age. Enalapril treatment significantly reduced hypercholesterolemia (247 +/- 41 vs. 102 +/- 13 mg/dl, p < 0.01, at 38 weeks) and proteinuria (766 +/- 290 vs. 206 +/- 119 mg/kg/day, p < 0.01, at 38 weeks). The glomerulosclerosis index (SI) was significantly higher in untreated control rats than in the enalapril-treated group (227 +/- 57 vs. 27 +/- 9, p < 0.01). Although we could not clarify whether hypercholesterolemia is a primary event or secondary to the nephrotic syndrome, these results indicate that the ACE inhibitor has the property to protect remnant glomeruli from glomerulosclerosis in male Imai rats as well as in other animal models in which focal and segmental glomerulosclerosis is believed to represent a common pathologic pattern. This rat strain represents a unique model of a spontaneous proteinuria which can provide an important information on the pathogenesis of human focal and segmental glomerulosclerosis.

Impaired Taste Acuity in Patients with Diabetes mellitus on Maintenance Hemodialysis

Aims: It has been reported that taste acuity for the four primary tastes, sour, sweet, salty and bitter, is impaired in hemodialysis (HD) patients. However, there have been no studies reported on taste acuity of diabetic HD patients. The present study aimed to quantify and compare the taste acuity of diabetic and non-diabetic HD patients, and further to determine if there were correlations between diminished taste acuity and certain blood serum parameters typically askew in hemodialysis patients. Methods: In a test group of 24 diabetic and 24 non-diabetic HD patients matched for age, body mass index and duration of HD, taste acuity for the four tastes was determined by asking patients to identify them at varying concentrations. Results: Statistical analyses indicate that bitter and total taste acuity were significantly impaired in diabetic HD patients. In diabetic HD patients, correlation was found between sweet, salty or total taste acuity and blood urea nitrogen or normalized protein catabolic rate. Conclusions: We conclude that taste acuity is partially impaired in diabetic HD patients, and suggest this contributes to reduced appetite, leading to malnutrition and poor prognoses.

Development of HTLV-I-associated myelopathy after blood transfusion in a patient with aplastic anemia and a recipient of a renal transplant

We report the development of rapid progressive HTLV-I-associated myelopathy (HAM) after blood transfusion in two immunosuppressed patients, one of whom had aplastic anemia and the other was the recipient of a renal transplant receiving immunosuppressive chemotherapy. Spastic paraparesis developed 11 or 16 months after transfusion and rapidly progressed to a wheelchair-bound state. The present 2 cases suggest that the coexistent immunosuppression may play an important role in the rapid development of HAM in transfusion-acquired cases.

Attenuating effect of a semipurified alcohol extract of soy protein on glomerular injury in spontaneous hypercholesterolemic male Imai rats

We investigated whether soy proteins alcohol-extractable components (SPEs; mainly consisting of isoflavones) have the ability to attenuate glomerular injury in male Imai rats of a spontaneous focal segmental glomerulosclerosis model. Male Imai rats were fed a casein-based diet with and without SPEs. Group 1 (Cont) was fed a standard diet without additional SPEs, and groups 2 (SPE-1) and 3 (SPE-2) were fed a standard diet supplemented with a semipurified alcohol extract of soy protein, 0.05 and 0.10 g/100 g of diet, respectively. Body weight, urinary protein level, serum constituents, and systolic blood pressure were evaluated every 4 weeks from 12 through 28 weeks of age. At 28 weeks of age, rats were studied morphologically. Growth rates were not different among the three groups throughout the experiment. SPE-supplemented diets resulted in less proteinuria and less hyperlipidemia. The decline in renal function shown by blood urea nitrogen and creatinine clearance was less marked in the animals fed the SPE-supplemented diets. Each SPE-supplemented diet equally induced less glomerular hypertrophy and less renal histological damage compared with nonsupplemented diets. The present study showed a beneficial effect of a semipurified alcohol extract of soy protein on glomerular disease.