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The present study was undertaken to assess the chronic effects of low dose octreotide (Oc) administration in rats with experimental diabetes mellitus (DM). Metabolic and clearance studies were performed in control normal rats, in rats with streptozotocin-induced DM of 1 week duration and in similar DM rats treated with Oc, 10-20 microg/day. Gene expression of IGF-I, IGF-I receptor (IGF-I R) and IGF-binding protein-1 (IGFBP-1) was examined in renal tissue from normal DM animals and DM animals treated with Oc 10, 20 and 100 microg/day. Seven days of Oc administration, 10 microg/day, in rats with experimental DM, was associated with enhanced hyperglycemia, increased glomerular filtration rate and urinary sodium excretion as compared with untreated DM animals. After a higher Oc dose, 20 microg/day, however, there were no significant changes in renal function and in glycemic control. Significant increases in kidney weight and kidney weight/body weight ratio were seen in DM rats as compared with control intact animals. These changes were not affected by Oc therapy in various doses. Induction of DM was associated with a marked increase in renal IGFBP-1 mRNA expression. There were no significant changes in the expression of IGF-I or IGF-I R mRNA. Oc therapy in a low or high dose did not affect gene expression of IGF-I, IGF-I R or IGFBP-1. Thus, the response to chronic low dose Oc administration of DM rats may vary from enhanced hyperglycemia and hyperfiltration to a lack of change in renal function or in glycemic control. Low dose Oc therapy was not associated with significant variations in renal mass or in the gene expression of IGF-I axis components. These findings are at variance with previously published studies which show a suppressive effect of Oc on renal function and growth in experimental diabetes. This apparent discrepancy may be related to the duration of treatment or to a biphasic physiological effect of Oc when used in different doses.
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ABSTRACT
Arginine vasopressin (AVP) stimulates Na+K+ ATPase and ornithine decarboxylase (ODC) activity in the rat medullary thick ascending limb. The effect of difluoromethyl ornithine (DFMO), a specific inhibitor of ODC activity, on AVP-stimulated Na+K+ATPase activity was evaluated using a cytochemical bioassay. Peaks in Na+K+ATPase activity in cultured rat renal segments which occurred after tissue had been exposed to 1 fmol AVP/l were completely inhibited by the addition of 20 mmol DFMO/l to the culture medium containing AVP. The addition of 20 mmol DFMO/l to the culture medium containing AVP in the concentration range 0·001–10 fmol/l inhibited completely the stimulation of Na+K+ATPase activity by AVP. The response of Na+K+ATPase to increasing doses of ATP (10–40 g polypeptide/l) was not influenced by the addition of 20 mmol DFMO/l to the culture medium containing AVP, suggesting that the prevention of AVP-stimulated Na+K+ATPase activity by DFMO was not due to a direct effect on the enzyme.
Journal of Endocrinology (1989) 121, 435–439
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ABSTRACT
The effect of age on the cyclic AMP (cAMP) response to increases in the concentration of arginine vasopressin in the presence of isobutyl methylxanthine (100 μmol/l) was studied in an in-vitro renal cell suspension prepared from C57BL/Icrfat mice at 6, 12, 18, 24, 29 and 35 months of age. Comparison of the response of the preparation to vasopressin, calcitonin and parathyroid hormone suggested that it was enriched with renal medullary cells. Basal cAMP output was similar throughout but the threshold dose of vasopressin increased from 1 × 10−11 mol/l (6, 12 and 18 months of age) to 1 × 10−10 mol/l (24, 29 and 35 months of age). The dose–response curve in 35-month-old mice was shifted to the right with the concentration of vasopressin required to give half maximal cAMP increased from 9·4 ± 0·37 × 10−11 mol/l (6 months) to 3·5±1·6 × 10−10 mol/l (35 months). Maximum cAMP output at 1 × 10 −9 mol/l was also reduced in the same animals (stimulated:basal ratio, 51·22±19·12 at 6 months; 11·50 ± 6·02 at 35 months). The results suggest that the lack of renal response to vasopressin in terms of cAMP metabolism may play a role in the well-documented age-related decline in urine-concentrating ability in experimental animals and elderly people.
J. Endocr. (1984) 103, 133–139
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Abstract
The significance of stress-induced hypogonadism remains unclear. Since plasma testosterone and LH have renotropic activity that is other than reproductive, we hypothesize that stress-induced hypogonadism is an adaptive response to protect the kidney. To examine this hypothesis, we prepared hypogonadal male rats with different levels of LH and testosterone through orchiectomy (castration), through chronic treatment with a slowly secreted form of gonadotropin-releasing hormone agonist (GnRHA; GnRHA pretreatment), or through both treatments concomitantly (castration with GnRHA pretreatment). Castrated rats had undetectable plasma testosterone and high plasma LH. GnRHA-pretreated rats had low plasma testosterone and normal plasma LH. Castrated rats with GnRHA pretreatment had undetectable plasma testosterone and normal plasma LH. We compared their sensitivity to HgCl2 nephrotoxicity and found that, when a low dose of HgCl2 (1·5 mg/kg body weight (BW)) was injected s.c. to induce acute renal failure, endogenous creatinine clearance (Ccr) decreased from 390 ± 30 to 94 ± 17 ml/h per kg BW in intact (unpretreated) rats. Such a decrease in Ccr was completely prevented in castrated rats (388 ± 30 ml/h per kg BW) and partially prevented in GnRHA-pretreated rats (216 ± 40 ml/h per kg BW). When a high dose of HgCl2 (2·25 mg/kg BW) was injected, half of the eight intact rats died but castrated rats and GnRHA-pretreated rats survived (P<0·05). The elevated resistance in castrated rats was reduced when plasma LH was reduced with GnRHA pretreatment, but was restored by additional pretreatment with ovine LH (40 μg/day), as evidenced by changes in Ccr. Elevated resistance in castrated rats was also reduced by the administration of testosterone propionate. In conclusion, hypogonadism activated the preventive and defensive mechanisms that protect the kidney through both decreased plasma testosterone and high or even normal plasma LH.
Journal of Endocrinology (1996) 148, 553–559
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Psammomys obesus, a desert rodent, develops diabetes when displaced from its natural environment and fed a high energy diet in the laboratory. This study was designed to examine variations in renal function in relation to the diabetic state with emphasis on changes in Na-K-ATPase activity. The following groups of Psammomys were studied: (1) Animals fed a saltbush diet; a low energy/high salt diet (natural). (2) Animals fed a low energy/low salt diet (laboratory). Both 1 and 2 were normoglycemic and normoinsulinemic and thus served as control. (3) Animals fed a high energy diet (group C) who were hyperglycemic and hyperinsulinemic; this group was divided into two subgroups: C1 presented with glomerular hyperfiltration rate and C2 with glomerular hypofiltration rate. (4) Animals fed a high energy diet presenting with hyperglycemia-hypoinsulinemia (group D). (5) Group D+I, similar to group D but treated with external insulin (2 U/24 h). Groups D and C1, whose glomerular filtration rose above normal by 30% and 70% respectively, exhibited metabolic similarity to Type I and Type II diabetes. In these groups, Na-K-ATPase activity in the cortex increased by 80-100% and in the medulla by 180% (P<0.001 vs control). In group C2 with reduced glomerular filtration rate (GFR), Na-K-ATPase activity did not differ from control. In group D+I, with normalized glomerular filtration rate, Na-K-ATPase activity was similar to control. There was a linear and significant correlation between GFR and Na-K-ATPase activity both in the cortex and in the medulla. These experiments present a well defined animal model of diabetes mellitus. Variations in glucose and in insulin did not correlate with Na-K-ATPase activity. These results clearly demonstrated that Na-K-ATPase activity in the diabetic Psammomys was determined by glomerular filtration but was independent of plasma glucose or insulin levels.
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A highly sensitive cytochemical method for the assay of the ability of plasma and extracts of human urine to stimulate renal glucose-6-phosphate dehydrogenase (G6PD) activity in vitro is described. In the proximal convoluted tubules there was a linear increase of G6PD activity with the logarithm of concentration of a highly purified natriuretic extract from normal human urine (0·384–384 ng active material/l) which was used as a standard. The stimulation of G6PD obtained with dilutions of normal human plasma was parallel to that produced by the standard. The sensitivity of the assay permitted the measurement of as little as 0·384 ng active material/l of the natriuretic extract (0·001 units/ml) and dilutions of 1/10 000 could be detected using normal human plasma. The mean ± s.e.m. index of precision was 0·068± 0·003 (n = 9).
It is known that inhibition of sodium potassium-dependent adenosine triphosphatase (Na+-K+-ATPase) is associated with a rise in G6PD activity. We have confirmed this observation by demonstrating that ouabain, a potent inhibitor of Na+ -K+-ATPase, stimulates renal G6PD activity in our assay and that natriuretic extract, human plasma and ouabain stimulated renal G6PD activity in vitro and simultaneously inhibited renal Na+-K+-ATPase activity in vitro.
The plasma from 12 normal subjects (five of whom were previously shown to inhibit renal Na+-K+-ATPase activity in vitro in a manner related to sodium intake) stimulated renal G6PD activity in vitro, and this activity was also directly related to sodium intake.
It is suggested that the change in the capacity of plasma to stimulate renal G6PD activity in vitro is a marker of the concentration of a circulating sodium transport inhibitor.
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ABSTRACT
The effect of extracellular calcium (Ca2+) on the cellular action of arginine vasopressin (AVP) was examined using an Na+, K+-ATPase inhibitor in rat renal papillary collecting tubule cells in culture. The pretreatment of cells with ouabain enhanced basal and AVP-induced cAMP production in a dose-dependent manner. The augmentation by ouabain of cellular cAMP production in response to AVP was totally abolished by co-treatment with cobalt, lanthanum, verapamil or Ca2+-free medium containing 1 mmol EGTA/l, each blocking cellular Ca2+ uptake by different mechanisms. Two other findings indicated that ouabain directly stimulated cellular Ca2+ mobilization; namely, that ouabain significantly increased 45Ca2+ influx and cellular free Ca2+ concentration ([Ca2+]i) determined by Fura-2 fluorescence. The ouabain-induced increase in [Ca2+]i was completely blocked by either cobalt or Ca2+-free medium containing 1 mmol EGTA/l. AVP at 0·1 μmol/l increased [Ca2+]i to 177·1 ±26·2 nmol/l from 92·2 ± 8·0 nmol/l (P<0·01) in renal papillary collecting tubule cells, and ouabain significantly enhanced the AVP-induced increase in [Ca2+]i. The increase of cellular free Ca2+ induced by ouabain probably binds to calmodulin to form an active complex of Ca2+-calmodulin in the cell, since two chemically dissimilar antagonists of calmodulin attenuated the enhancement by ouabain of cAMP production in response to AVP. These results therefore indicate that ouabain increases cellular Ca2+ uptake and enhances AVP-induced cellular free Ca2+ mobilization and its own second messenger cAMP production in renal papillary collecting tubule cells, and that extracellular Ca2+ is an important source for ouabain-mobilized cellular Ca2+.
Journal of Endocrinology (1989) 121, 467–477
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SUMMARY
A case is described in which the presence of an adrenal cortical adenoma was predicted from the association of hypertension, hypokalaemia, raised aldosterone secretion and depressed plasma renin concentration.
Pre-operatively, administration of a spironolactone for a period of 10½ months corrected the electrolyte abnormalities, increased the plasma renin concentration to normal and lowered the blood pressure, although the raised aldosterone secretion was unchanged.
At operation a typical adrenal cortical adenoma was found.
Renal biopsy at operation showed arteriolar fibrinoid lesions, although no retinal lesions were seen at any stage.
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ABSTRACT
Previous studies have indicated that ornithine decarboxylase (ODC) may be involved in the stimulation of Na+/K+-ATPase activity by arginine vasopressin (AVP) in the rat renal medullary thick ascending limb of Henle's loop. The present study was aimed at establishing the role of the polyamines, the conversion products of ODC activity, in the stimulation of Na+/K+-ATPase by AVP. Using cytochemical methods, we have demonstrated an increase in Na+/K+-ATPase activity after stimulation with putrescine, spermidine and spermine (each 1 mmol/l) for 2·5,2 and 1·5 min respectively. The specific inhibitors of spermidine and spermine synthase, bis-cyclohexylammonium sulphate and N-alkylated-1,3-diaminopropane respectively, inhibited the stimulation of Na+/K+-ATPase by AVP, this inhibition being reversed by spermine. These findings suggest that polyamines are involved in the stimulus-response coupling of the hormone-mediated response.
Journal of Endocrinology (1990) 127, 377–382
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The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.
