Impairment of renal compensatory hypertrophy by hypothyroidism in the rat

Renal compensatory hypertrophy (RCH) occurs in hypothyroid rate, but it is impaired when compared to RCH found in euthyroid controls. It is due to cellular hypertrophy as the DNA content does not change and the Protein/DNA ratio increases in the compensating kidney. RCH is enhanced by thyroxine (T4) with a rise in the DNA content of the compensating kidney, but the Protein/DNA ratio does not change indicating that hypertrophy is as important as hyperplasia. Corticotrophin (ACTH) given to eu and hypothyroid rats enhances RCH with an increase in the protein content of the compensating kidney without any change in its DNA content. In the hyperthyroid rats, the enhanced RCH is not further increased by ACTH and the rise in the kidney DNA content elicited by T4 is suppressed by ACTH. The Protein/DNA ratio is increased by ACTH in hypo, eu and hyperthyroid rats. The renotrophic action of ACTH is due to hyperadrenocorticism: it is related to an increased plasma testosterone level and to a disturbed Na+, K+ and glucose metabolism.     

Influence of nutritional factors on the renotrophic action of ACTH in the uninephrectomized rat.

In the rat, renal compensatory hypertrophy (RCH) was apparent 48 h after uninephrectomy; it was significantly enhanced by long-acting beta1-24-corticotrophin (ACTH) when the animals had free access to food and a NaCl solution (9 g/l). In rats starved after uninephrectomy but drinking the NaCl solution freely, RCH was suppressed: the weights of the body, heart, liver, and solitary kidney were reduced. In similarly starved rats treated with ACTH, the weights of the heart and the solitary kidney were normal. RCH was also impaired in rats fed only a glucose solution (30 g/dl) after uninephrectomy, but it is restored by ACTH, which significantly increases the weight of the remaining kidney. This renotrophic action of ACTH may be related to hyperglycemia and, perhaps, elevated urinary K excretion, which occur in hyper-adrenocorticism and increase the work load of the nephron.     

Histomorphometric study of the enhancement of renal compensatory hypertrophy by ACTH in the rat

In the female adult rat, renal compensatory hypertrophy is greatly enhanced by hyperadrenocorticism elicited by the administration of ACTH given at a dose of 18 Y/100 g BW/d for 7 days after uninephrectomy (UN). This renotrophic effect of ACTH is particularly prominent in rats drinking a NaCl solution (9 g/l). In the present experiments, we performed histomorphometrical measurements of the glomerular tuft (GT) and the proximal tubule (PT) in the hypertrophying kidney (HK) remaining 7 days after UN in 10 rats treated with ACTH and 7 control animals. The histologic preparations were examined under light microscopy with the "Kontron" image analyzer. ACTH increased the weight of the HK (1213.8 +/- 20.3 mg versus 1037.3 +/- 13.3, p less than 0.001) and determined an enlargement of the cross sectional area of the GT (12559 +/- 3351.3 mu2 versus 10486 +/- 407.5, p less than 0.01) and of the epithelial area of the PT (1751 +/- 40.8 mu2 versus 1586 +/- 41.5, p less than 0.025). These morphometrical data are consistent with the increased Protein/DNA ratio - a marker of cellular hypertrophy - found in other rats studied under the same experimental conditions. The increased weight gain of the HK elicited by ACTH is related to the hypertrophy of the epithelial cells of the PT and possibly to an enlargement of the glomeruli.     

Effects of fasting and of ACTH on renal compensatory hypertrophy in the 48 hour uninephrectomized rat]

Renal compensatory hypertrophy (R.C.H.) is determined 48 h. after uninephrectomy in fed and fasting rats having free access to a NaCl solution. ACTH (18 gamma/100 g BW/d/2d) enhances R.C.H. in the fed animals. R.C.H. is severely impaired by food deprivation and the remaining kidney looses weight; a normal kidney weight can be maintained if the fasted, uninephrectomized rat is treated with ACTH. These experiments suggest that the stimulation of the adrenal cortex by ACTH has a renotrophic effect. This action may be related to the elevation of blood glucose or/and to the fall of the concentration of plasma K+.     

高热量高蛋白饮食诱导GK大鼠糖尿病肾病模型的建立

目的运用高热量高蛋白饮食诱导GK大鼠2型糖尿病肾病模型的建立,并探讨其可能的作用机制。方法 28周龄GK大鼠24只,随机分成对照组、模型组,每组各12只,模型组给予高热量高蛋白饮食,对照组给予正常饮食,共8周。于第0、4、8周观察24 h尿微量白蛋白、24 h尿蛋白、尿肌酐、尿微量白蛋白/尿肌酐比值水平;于第0、8周观察空腹血糖和血清肌酐、尿素氮、总胆固醇、甘油三脂、一氧化氮水平;实验结束时取双肾称重并计算肾肥大指数,取肾组织观察病理形态学变化,检测肾组织钠钾ATP酶活性。结果与对照组比,模型组大鼠24 h尿微量白蛋白、24 h尿蛋白、尿微量白蛋白/尿肌酐比值、空腹血糖、总胆固醇、甘油三脂、一氧化氮、肾肥大指数水平和肾组织钠钾ATP酶活性显著提高,模型组肾小球体积增大,系膜基质增生,基底膜增厚明显。结论运用高热量高蛋白饮食诱导GK大鼠可成功建立2型糖尿病肾病模型。血糖血脂的上升是糖尿病肾病形成的重要因素,同时钠钾ATP酶活性增强进一步损伤肾小管功能,一氧化氮升高促使肾小球高灌注、高滤过,也是加速GK大鼠肾病形成的原因。     

Excretion of water, sodium, and potassium during the compensatory renal hypertrophy in hypothyroid rats]

Renal compensatory hypertrophy is studied in age matched euthyroid and radiothyroidectomized female rats. 7 days after uninephrectomy, the hypertrophy of the remaining kidney is equally small in both groups. But 60 days after this operation, the hypothyroid animals show only a 12% increase in the wet weight of the remaining kidney whereas the euthyroid controls increase this weight by 21%. The excretion of water, Na and K are determined in the urine excreted in 5 h after a small water load. The results are related to 1 gram of kidney wet weight. These outputs increase in all animals after uninephrectomy. They are significantly higher in the hypothyroid rats than in the euthyroid controls as well before than 60 days after uninephrectomy. The reduction in tubular Na reabsorption found in the hypothyroid rat may account for the impairment of compensatory renal hypertrophy in hypothyroidism.     

Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner

The adrenal gland is an essential stress-responsive organ that is part of both the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullary system. Chronic stress exposure commonly increases adrenal weight, but it is not known to what extent this growth is due to cellular hyperplasia or hypertrophy and whether it is subregion specific. Moreover, it is not clear whether increased production of adrenal glucocorticoid after chronic stress is due to increased sensitivity to adrenocorticotropic hormone (ACTH) vs. increased maximal output. The present studies use a 14-day chronic variable stress (CVS) paradigm in adult male rats to assess the effects of chronic stress on adrenal growth and corticosterone steroidogenesis. Exogenous ACTH administration (0-895 ng/100 g body wt) to dexamethasone-blocked rats demonstrated that CVS increased maximal plasma and adrenal corticosterone responses to ACTH without affecting sensitivity. This enhanced function was associated with increased adrenal weight, DNA and RNA content, and RNA/DNA ratio after CVS, suggesting that both cellular hyperplasia and hypertrophy occurred. Unbiased stereological counting of cells labeled for Ki67 (cell division marker) or 4,6-diamidino-2-phenylindole (nuclear marker), combined with zone specific markers, showed that CVS induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Collectively, these results demonstrate that increased adrenal weight after CVS is due to hyperplasia and hypertrophy that occur in specific adrenal subregions and is associated with increased maximal corticosterone responses to ACTH. These chronic stress-induced changes in adrenal growth and function may have implications for patients with stress-related disorders.     

Comparative characteristics of compensatory renal hypertrophy following unilateral nephrectomy in mature and old rats]

One of the kidneys was removed in rats from 35 to 900 g in weight; they were then sacrificed 2, 14, 30 and 60 days after the operation. The degree of compensatory hypertrophy of the remaining kidney varied greatly in rats of different age, without decreasing in old age, however. Sixty days after the operation the weight of the hypertrophic kidney in old rats was equal to 55--93% of the weight of both kidneys in control. Hypertrophy of the kidney at any age was accompanied by an increased proliferation of the tubular cells, particularly in their proximal portion. An increase in the size of renal bodies during kidney hypertrophy was characteristic of rats of any age. However, with the advance of age this process developed more rapidly and was stronger. At any periods of investigation the hypertrophic kidney in rats of any age contained a greater number (1 1/2--2 times more) of "open" renal bodies in comparison with the kidney of intact rats.     

Levels of lipid peroxidation, superoxide dismutase, and Na+/K+ ATPase in some tissues of rats exposed to a Nigerian-like diet and cadmium

The purpose of the present study was to examine the role of a wholly compounded Nigerian-like diet on the activities of superoxide dismutase (SOD) and Na+/K+ ATPase and level of lipid peroxidation in oral cadmium toxicity. Nine-week-old Wistar albino rats (100 +/- 2.0 g) were exposed to 100 ppm cadmium in drinking water and the Nigerian-like diet (low in protein and high in carbohydrates and fiber) for 16 wk. The results obtained indicate that cadmium reduced weight gain and increased fecal output of rats, which was further potentiated by the Nigerian-like diet. Cadmium was concentrated in the intestine, liver, and kidney, with the highest level observed in the kidney, followed by the liver. The Nigerian-like diet reduced the concentration of cadmium in these tissues. Cadmium increased lipid peroxidation and inhibited SOD and Na+/K+ ATPase in the tissues. These were also aggravated in rats fed the Nigerian-like diet. Because the Nigerian-like diet increased lipid peroxidation and inhibited SOD and Na+/K+ ATPase in the tissues, it rendered rats more susceptible to cadmium toxicity.     

Effect of chronic ethanol consumption on postnatal development of renal (Na + K)-ATPase in the rat.

Renal (Na + K)-ATPase was studied to ascertain whether it follows the pattern of adaptation of membrane-bound enzymes that are inhibited by acute ethanol exposure and develop greater activity after chronic ethanol treatment. A colony of rats was given 20 per cent (v/v) ethanol as sole drinking solution throughout gestation, lactation and following weaning. (Na + K)-ATPase and ouabain-insensitive Ca(2+)-ATPase activities were determined; regional distribution of these enzymes was assessed in renal cortex and outer medulla. Control rats drank tap water. (Na + K)-ATPase in whole homogenate of kidney increased with age in controls and ethanol-fed rats, but the latter showed higher values at every age studied. Between 15 and 60 days of age, the control group showed 2-fold increases in cortex and 5-fold in outer medulla, whereas ethanol-fed rats reached a 3-fold increase in the enzyme activity in both renal regions. Ca(2+)-ATPase showed the same time course in developing kidney of both groups. Chronic ethanol treatment of adult rats resulted in an increase of (Na + K)-ATPase activity in cortex and outer medulla, but no change in other ATPases. Since an earlier maturational development of renal (Na + K)-ATPase was displayed by ethanol-fed rats, underlying mechanisms that may account for these results are discussed.     

Stimulatory effect of calcium administration on regucalcin mRNA expression is attenuated in the kidney cortex of rats ingested with saline

The expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats ingested with saline was investigated. The alteration in regucalcin mRNA levels was analyzed by Northern blotting using liver regucalcin complementary DNA (0.9 kb of open reading frame). Rats were freely given saline as drinking water for 7 days. Regucalcin mRNA levels in the kidney cortex were suppressed by saline ingestion. When calcium chloride (10 mg Ca/100 g body weight) was intraperitoneally administered to rats ingested with saline for 7 days, the effect of calcium administration to increase regucalcin mRNA levels was weakened by saline ingestion. Such effect was also seen by the administration of 2.5 and 5 mg Ca/100 g. Regucalcin mRNA levels in the kidney cortex of spontaneous hypertensive rats (SHR) were not appreciably increased by the administration of calcium (10 mg/100 g). Meanwhile, calcium content in the kidney cortex was significantly elevated by the administration of calcium (10 mg/100 g) to normal rats. This increase was weakened in saline-ingested rats. Moreover, Ca²⁺/calmodulin-dependent protein kinase activity in the cytosol of kidney cortex was significantly decreased by saline ingestion. These results suggest the possibility that saline ingestion-induced suppression of regucalcin mRNA expression in the kidney cortex is partly involved in the attenuation of Ca²⁺ signalling.     

Hypertrophic response of the kidney in indomethacin treated rats.

Indomethacin, a potent inhibitor of prostaglandin (PG) synthesis administered to rats in a total dose of 2 x 4.5 mg/kg i.v. for 2 days enhanced compensatory renal hypertrophy following unilateral nephrectomy (UN). The same drug given to rats with intact kidneys in a total dose of 4 x 4.5 mg/kg i.p. in 2 days increased kidney weight renal RNA content and decreased renal acidic ribonuclease activity. It remains to be elucidated whether the suppression of PG synthesis and/or other pharmacological effects of indomethacin account for these findings.     

Magnesium: Effects on reperfusion arrhythmias and membrane potential in isolated rat hearts

Myocardial Na+,K+-ATPase was studied in patients with aortic valve disease, and myocardial Na+,K+- and Ca2+-ATPase were assessed in spontaneously hypertensive rats (SHR) and hereditary cardiomyopathic hamsters using methods ensuring high enzyme recovery. Na+,K+-ATPase was quantified by [3H]ouabain binding to intact myocardial biopsies from patients with aortic valve disease. Aortic stenosis, regurgitation and a combination hereof were compared with normal human heart and were associated with reductions of left ventricular [3H]ouabain binding site concentration (pmol/g wet weight) of 56, 46 and 60%, respectively (p < 0.01). Na+,K+ and Ca2+-ATPases were quantified by K+- and Ca2+-dependent p-nitrophenyl phosphatase (pNPPase) activity determinations in crude myocardial homogenates from SHR and hereditary cardiomyopathic hamsters. When SHR were compared to age-matched Wistar Kyoto (WKY) rats an increase in heart-body weight ratio of 75% (p < 0.001) was associated with reductions of K+- and Ca2+-dependent pNPPase activities (mol/min/g wet weight) of 42 (p < 0.01) and 27% (p < 0.05), respectively. When hereditary cardiomyopathic hamsters were compared to age-matched Syrian hamsters an increase in heart-body weight ratio of 69% (p < 0.001) was found to be associated with reductions in K+- and Ca2+-dependent pNPPase activities of 50 (p < 0.001) and 26% (p = 0.05), respectively. The reductions in Na+,K+- and Ca2+-ATPases were selective in relation to overall protein content and were not merely the outcome of increased myocardial mass relative to Na+,K+- and Ca2+-pumps. In conclusion, myocardial hypertrophy is in patients associated with reduced Na+,K+-ATPase concentration and in rodents with reduced Na+,K+- and Ca2+-ATPase concentrations. This may be of importance for development of heart f in hypertrophic heart disease.     

Ethanol and leucine oxidation--II. Leucine oxidation by rat tissue in vitro

The effect of ethanol upon leucine oxidation by rat tissues in vitro is reported. The activities of branched chain amino acid aminotransferase and 2-oxo acid dehydrogenase were decreased by chronic administration of ethanol (20% v/v solution as drinking water for 35 d) in muscle and kidney but were increased, although not significantly, in liver. Acute administration of ethanol (8 g kg-1 body-weight 0.73) did not affect enzyme activities. Tissue NAD+:NADH ratios, calculated from lactate:pyruvate ratios, were significantly decreased in the liver and kidney of rats receiving ethanol acutely. These data are consistent with the view that ethanol decreases leucine oxidation by decreasing availability of NAD+ when given acutely and by decreasing enzyme activity when administered chronically.     

Expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats: The stimulation by calcium administration

The expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats was investigated. The change of regucalcin mRNA levels was analyzed by Northern blotting using liver regucalcin complementary DNA (0.9 kb of open-reading frame). Regucalcin mRNA was expressed in the kidney cortex, and this expression was clearly increased by a single intraperitoneal administration of calcium chloride solution (5–15 mg Ca/100 g body weight) in rats; this increase was remarkable at 60–120 min after the administration. Thyroparathyroidectomy (TPTX) caused a slight decrease of regucalcin mRNA levels in the kidney cortex. However, the administration of calcium (10 mg/100 g) in TPTX rats produced a clear increase of regucalcin mRNA levels in the kidney cortex. The subcutaneous administration of calcitonin (10–100 MRC mU/100 g) or parathyroid hormone [1–34] (1–10 U/100 g) in TPTX rats which received calcium (10 mg/100 g) administration did not cause an appreciable alteration of regucalcin mRNA levels in the kidney cortex, suggesting that the mRNA expression is not stimulated by calcium-regulating hormones. The administration of trifluoperazine (TFP; 5 mg/100 g), an inhibitor of Ca²⁺/calmodulin action, completely blocked the expression of regucalcin mRNA stimulated by calcium administration. Now, calcium content in the kidney cortex was significantly elevated by a single intraperitpneal administration of calcium (10 mg/100 g) in rats. The present study clearly demonstrates that the expression of regucalcin mRNA in the kidney cortex is stimulated by calcium administration in rats. This expression may be mediated through Ca²⁺/calmodulin action in the kidney cortex.     

Effect of saline solutions administered parenterally in different postoperation phases on the regeneration of rat liver after partial hepatectomy

Two series of experiments were carried out on female laboratory rats with a mean pre-operation weight of 250 +/- 30 g, fed up to the time of the experiment on a standard laboratory diet with water ad libitum. In the first series the rats were subjected to 65-70% partial hepatectomy (PH) or to laparotomy (LAP) and their serum Na+, K+, Cl- and total calcium concentrations were determined 6, 12, 18 and 24 h after the operation. At given postoperation intervals the serum Na+, Cl- and total calcium concentrations in hepatectomized animals were lower than in the intact controls, while the K+ concentration was higher. In the second series of experiments, the rats were given infusions of physiological saline or Ringer solution at different intervals (1-6, 7-12, 1-12 and 1-24 h) after PH. Specific DNA activity in the liver, the hepatocyte mitotic index, the total DNA content of the liver and other indicators show that physiological saline infusions had an inhibitory, or at most a neutral effect on the initiation of liver regeneration, while the effect of the infusion of Ringer solution on the initiation of liver regeneration, in most of the given intervals, was indifferent. The regeneration response depends on the post-PH phase in which the solution is infused.     

Suppressed expression of calcium-binding protein regucalcin mRNA in the renal cortex of rats with chemically induced kidney damage

The alteration of Ca²⁺-binding protein regucalcin mRNA expression in the kidney cortex of rats administered cisplatin and cephaloridine, which can induce kidney damage, was investigated. Cisplatin (0.25, 0.5 and 1.0 mg/100 g body weight) or cephaloridine (25, 50 and 100 mg/100 g) was intraperitoneally administered in rats, and 1, 2 and 3 days later they were sacrificed. The alteration in serum findings after the administration of cisplatin (1.0 mg/100 g) or cephaloridine (50 and 100 mg/100 g) demonstrated chemically induced kidney damage; blood urea nitrogen (BUN) concentration increased markedly and serum inorganic phosphorus or calcium concentration decreased significantly. Moreover, the administration of cisplatin (1.0 mg/100 g) or cephaloridine (100 mg/100 g) caused a remarkable increase of calcium content in the kidney cortex of rats, indicating kidney damage. The expression of regucalcin mRNA in the kidney cortex was markedly reduced by the administration of cisplatin or cephaloridine in rats, when the mRNA levels were analyzed by Northern blotting using rat liver regucalcin cDNA (0.9 kb). The mRNA decreases were seen with the used lowest dose of cisplatin or cephaloridine. The present study clearly demonstrates that the mRNA expression of Ca²⁺-binding protein regucalcin in the kidney cortex of rats is decreased by chemically induced kidney damage.     

Enhancement of compensatory renal hypertrophy by beta-1-24 corticotropin in the rat]

In the rat, the administration of beta1-24-corticotrophin during 7 days following an uninephrectomy enhances significantly the compensatory hypertrophy of the remaining kidney. There is no increase in renal compensatory hypertrophy when ACTH is injected to previously adrenalectomized rats. This action of ACTH could be related to the diabetes mellitus induced by this hormone or to an increase in sodium reabsorption by the tubular epithelial cells.     

Somatomedin-C in the kidney of streptozotocin diabetic rats

To evaluate the possible role of somatomedin-C, insulin-like growth factor I, in renal hypertrophy in early diabetes, kidney tissue SmC concentrations were measured in streptozotocin-induced (80 mg/kg ip) diabetic rats. Body weight, liver weight, plasma SmC concentration, and SmC concentration in the liver of diabetic rats were significantly lower than those of controls. Seven days after induction of diabetes, the kidney weight (898 +/- 95 mg) in diabetic rats was significantly greater than that in controls (755 +/- 69 mg), while SmC concentration in the kidney of diabetic rats (1.7 +/- 0.3 U/g kidney) was significantly lower than that of control rats (5.4 +/- 0.6 U/g kidney). These results suggest that renal SmC may not have an important role in renal hypertrophy in early stages of diabetes and that renal production of SmC may be impaired by insulin deficiency in rats.     

The measurement of intracellular sodium activities in the bullfrog by means of double-barreled sodium liquid ion-exchanger microelectrodes.

A double-barreled Na+-selective microelectrode was constructed with monensin as a liquid ion exchanger. The HCl-treated monensin was dissolved in a solvent (Corning 477317) at 10% (weight/weight). Internal reference solution of its ionic barrel was mixture of 0.49 M NaCl and 0.01 M KCl, the pH being adjusted to 3 with 0.1 M citrate-HCl buffer, whereas that of the PD barrel was 0.5 M KCl. Average slope and selectivity ratio (Na+/K+) tested on 10 different microelectrodes were -57.5 +/- 1.87 mV/P(Na) (SEM) and 6.7 +/- 0.44, respectively. The electrical resistance was an order of 10(10) ohm and the response time was less than 10 sec. Using this microelectrode, a free flow micropuncture experiment was carried out in the bullfrog kidney and the intracellular Na+ activity as well as the membrane PD was determined on the proximal tubular cell. Average value (+/- SEM, n = 15) for the intracellular Na+ and K+ was 20.7 +/- 1.56 mEq/L and 61.2 +/- 1.16 mEq/L, respectively, and -68.7 +/- 0.88 mV for the peritubular membrane PD. There was a significant negative correlation between Na+ and K+ activities within the cell, i.e., the lower the ionic activity of cellular Na+ was, the higher the cellular K+, and vice versa, the sum of these two being kept nearly constant. The above finding may be somehow related to the isosmosis in the reabsorptive process across the proximal tubular epithelium.