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Article

Insulin-Like Growth Factor-I Stimulates Renal 1,25-Dihydroxycholecalciferol Synthesis in Old Rats Fed a Low Calcium Diet¹

The Open Laboratory of Asymmetric Synthesis, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong, P.R.C. and ^* Sections of Endocrinology and Nephrology, Department of Medicine, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637

²To whom correspondence should be addressed.

	ABSTRACT

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The adaptive increase in renal proximal tubule 25-hydroxyvitamin D--hydroxylase activity (1-OHase) during dietary calcium restriction is mediated by an increase in parathyroid hormone (PTH) and is inhibited by aging. Recent studies in mature (3–4 mo) rats demonstrated that insulin-like growth factor-I (IGF-I) restored stimulation of renal 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] production by low phosphorus diet (LPD), another major stimulus of 1-OHase. These studies were designed to determine whether IGF-I stimulates 1-OHase during low calcium intake in old rats. Male rats were fed a normal calcium diet (NCD, 6 g Ca/kg diet) or low calcium diet (LCD, 0.2g Ca/kg diet) for 14 d, and recombinant human IGF-I [rhIGF-I, 1.4 mg/(24h 160 kg body wt)] or vehicle was administrated via miniosmotic pump for 72 h before killing. In 4-mo-old male Sprague-Dawley rats, LCD increased in vitro renal 1-OHase activity in the presence but not in the absence of rhIGF-I. LCD increased in vitro1-OHase activity in young (1-mo-old) but not old (24-mo-old) male Fischer 344 rats. RhIGF-I increased 1-OHase activity in 24 mo-old rats fed LCD to levels that were not different from those in 1-mo-old rats fed LCD. The results indicate that the adaptive increase in 1-OHase activity due to a LCD is lost by 4 mo in rats and can be restored by pharmacologic doses of rhIGF-I.

KEY WORDS: • rats • aging • low calcium diet • 1,25-dihydroxycholecalciferol • kidney

	INTRODUCTION

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The efficiency of intestinal calcium absorption varies with the skeletal requirements for this mineral. Conditions that increase calcium needs, such as low dietary calcium intake, increase the efficiency of intestinal calcium absorption in humans (Heaney et al. 1977 , Ireland and Fordtran 1973 , Nicolaysen 1943 ) and vitamin D–dependent active calcium transport in rats (Favus 1985 , Pansu et al. 1981 ) through an increase in renal 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃]³ biosynthesis (Armbrecht et al. 1980a , Favus and Langman 1986 ). Advancing age is accompanied by a loss of the adaptive increase in intestinal calcium transport during dietary calcium deprivation (Armbrecht et al. 1979 and 1980b , Ireland and Fordtran 1973 ). Such loss of adaptive response is due to the decrease in renal 25-hydroxyvitamin D-1--hydroxylase (1-OHase) activity (Armbrecht et al. 1980a , 1982 and 1984 ). As a consequence, low calcium intake results in a negative calcium balance and bone loss (Armbrecht et al. 1981 , Heaney et al. 1977 , Nicolaysen 1943 ). Parathyroid hormone (PTH) is a major regulator of the renal proximal tubule 1-OHase (Garabedian et al. 1972 , Rasmussen et al. 1972 ), and modulates the changes in 1,25(OH)₂D₃ and calcium transport in response to variations in dietary calcium intake (Rader et al. 1979 , Treschel et al. 1980 ). However, in old animals, elevated endogenous PTH or administration of pharmacologic doses of PTH fails to increase circulating 1,25(OH)₂D₃ or in vitro renal 1-OHase activity (Armbrecht et al. 1982 , and 1984 , Friedlander et al. 1994 ).

Previous studies in old rats have demonstrated that the phospholipase C/protein kinase C and cAMP/protein kinase A signaling pathways, which mediate PTH control of 1,25(OH)₂D₃ production (Janulis et al. 1992 ), are intact in rat renal proximal tubules (Friedlander et al. 1994 ). Whether the age-induced resistance of PTH-mediated 1,25(OH)₂D₃ production results from an irreversible loss of the 1-OHase enzyme complex is unknown. Insulin-like growth factor I (IGF-I) administration has been shown to raise serum 1,25(OH)₂D₃ levels in rats (Caverzasio et al. 1990 ) and increase 1-OHase activity in mice (Nesbitt and Drezner 1993 ) and in cultures of renal proximal tubule cells (Condamine et al. 1994 , Menaa et al. 1995 ). Our recent studies also demonstrated that pharmacologic doses of IGF-I [1.4 mg/(kg body wt·d)] stimulated renal 1-OHase activity in 4-mo-old rats during dietary phosphorus restriction, another major regulator of 1-OHase (Wong et al. 1997 ). These studies were undertaken to determine whether the loss of 1-OHase activity is reversible and whether IGF-I can increase 1-OHase activity during LCD in both 4- and 24-mo-old rats.

	MATERIALS AND METHODS

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Animals and diets.

In Experiment 1, 4-mo-old male Sprague-Dawley rats (320 to 350g) were randomly assigned to four groups: NCD-V group, in which rats were fed normal calcium diet (NCD, Harlan Teklad, Madison, WI) and infused with vehicle (V; 1 mg/L bovine serum albumin in 0.1 mol/L acetic acid) via miniosmotic pump; NCD-I group, in which rats were fed NCD and infused with IGF-I [I; 1.4 mg/(kg body weight·d)]; LCD-V group, in which rats were fed a low calcium diet (LCD, Harlan Teklad, Madison, WI) and infused with vehicle; and LCD-I group, in which rats were fed LCD and infused with IGF-I. Rats had free access to their respective diets for 14 d. Both diets contained 2.4 g Mg/kg diet and 2.2 IU cholecalciferol/g, which is sufficient to maintain normal serum 25-hydroxycholecalciferol levels. The composition of the diets is shown in Table 1 . The duration of IGF-I infusion was 72 h; it was delivered by miniosmotic pumps (model 1003D, Alza, Palo Alto, CA) during the last 72 h before rats were killed by exsanguination via the abdominal aorta while under deep ether anesthesia. Recombinant human (rh)IGF-I and vehicle were loaded into miniosmotic pumps and equilibrated in saline for 12 h to obtain the desired flow rate. The pumps were then implanted subcutaneously while the animals were under light ether anesthesia. The dosage of rhIGF-I and the duration of infusion were selected because this regimen normalized 1-OHase activity in old rats fed a low phosphorus diet (Wong et al. 1997 ).

Serum and urine chemistries.

Serum calcium, phosphorus, creatinine and glucose, and urine creatinine were measured using a Beckman CX5 autoanalyzer (Beckman Instruments, Fullerton, CA). Serum PTH was measured in duplicate by a rat-specific RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Other aliquots of serum were subjected to acid-ethanol extraction (ethanol and 2 mol/L HCl, 87.5:12.5) to remove interfering IGF binding proteins. The samples were then assayed in duplicate using a RIA kit that employs human standard IGF-I and primary anti-human IGF-I antibody (Nichols Institute Diagnostics). A 24-h urine collection was obtained after the rats had been equilibrated in individual metabolic cages for 1 d. Creatinine clearance was calculated from serum and urine creatinine. Proximal tubule protein concentration was measured by the method of Lowry et al. (1951) .

Preparation of renal proximal tubules.

An enriched preparation of renal proximal tubules was prepared by a modification (Favus and Langman 1986 ) of the procedure of Vinay et al. (1981) . Briefly, rats were placed under deep ether anesthesia and exsanguinated via the abdominal aorta. Both kidneys were removed, bisected and washed in ice-cold Krebs-Hanseleit buffer (KHS, pH 7.4). Medullary tissue was discarded, and cortical slices were incubated in the presence of collagenase (Type I, > 125 U/mg dry weight; Worthington Biochemical, Freehold, NJ) and bovine serum albumin for 45 min at 37°C. The digest was then layered onto a gradient of 45% Percoll in KHS (pH 7.4, 300 mOsm/kg), maintained in an atmosphere of O₂/CO₂ (95:5). The suspension was then centrifuged at 10,200 x g for 30 min at 4°C; the layer enriched in proximal tubules was removed, washed twice with ice-cold KHS buffer, suspended in KHS buffer and placed on ice until used in the 1-OHase assay.

Measurement of 1-OHase activity.

Proximal tubules (1–2 mg protein) were suspended in 1.5 mL KHS in Erlenmeyer flasks, maintained at 37°C and gassed with O₂/CO₂ (95:5). After 30 min of preincubation, the reaction was begun by the addition of 10 µmol/L 25-hydroxycholecalciferol substrate in 5 µL ethanol. To study 1-OHase activity under conditions of zero-order kinetics, the reaction was halted after 5 min by the addition of 1.0 mL acetonitrile (Langman et al. 1985 ). 1-OHase activity was expressed as 1,25(OH)₂D₃ produced in pg/(mg tubule protein·5 min).

1,25(OH)2D3 assay.

1,25(OH)₂D₃ was assayed in duplicate in acetonitrile extracts of serum or proximal tubule homogenate using a vitamin D receptor-based assay as previously described (Favus and Langman 1986 ). Intra- and interassay CV in nine consecutive assays were 11 and 16%, respectively.

Materials.

25-Hydroxycholecalciferol was a gift from Organon (West Orange, NJ). 1,25(OH)₂D₃ was kindly provided by Dr. Milan R. Uskokovic (Roche Laboratories, Nutley, NJ). [H³]-1,25(OH)₂D_3, specific activity 110–120 Bq/mmol, was purchased from Amersham Searle (Arlington Heights, IL). Recombinant human IGF-I (rhIGF-I) was a generous gift from Genentech (South San Francisco, CA). Miniosmotic pumps were purchased from Alza, Palo Alto, CA; and Percoll from Pharmacia Biotech, Piscataway, NJ.

Statistical analysis.

Data are reported as means ± SEM In Experiment I, the significance of differences between group means was determined by one-way ANOVA when more than two groups were compared. When the F-ratio of the one-way ANOVA reached P 0.05, then further analysis was performed using Tukey’s test (Systat Version 8.0, SPSS, Chicago, IL). In Experiment 2 in which 1- and 24-mo-old groups were compared for diet effect and in which 24-mo-old rats were compared for diet and IGF-I effects, 2 x 2 factorial designs were analyzed by two-way ANOVA. When the F-ratio of the two-way ANOVA reached P 0.05, then post-hoc tests of means were conducted using the Bonferroni Correction (Systat Version 8.0). Because serum IGF-I levels showed heterogeneity across groups (Tables 2 and 3) , each value was subjected to log₁₀ transformation before ANOVA analysis. Group means differing by P-values 0.05 were considered significant.

	RESULTS

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View larger version (18K): [in this window] [in a new window]   Figure 1. In vitro 25-hydroxyvitamin D 1--hydroxylase (1-OHase) activity in renal proximal tubules prepared from 4-mo-old male Sprague-Dawley rats fed either a normal calcium diet (NCD, 6 g Ca/kg diet) or low calcium diet (LCD, 0.2 g Ca/kg diet) for 14 d and infused with either recombinant human insulin-like growth factor (IGF)-I [I, 1.4 mg/(24 h·kg body wt)] or vehicle (V) for 72 h before killing. Values are means ± SEM of individual measurements in each rat (n = 8 in each of the following groups: NCD-V; NCD-I; LCD-V; and LCD-I).. *Significantly greater than other means, P < 0.005.

In Experiment 2, in vitro 1-OHase activity was readily detectable in proximal tubules from 1- and 24- mo-old Fischer 344 rats fed NCD (Fig. 2 ). Renal proximal tubule 1-OHase activity in 1-mo-old rats fed LCD was 100% greater than that in rats fed NCD (Fig. 2) , whereas 1-OHase activity in 24-mo-old rats fed LCD was not different than that of 24 mo-old rats fed NCD. In 24 mo-old rats fed NCD and infused with rhIGF-I, in vitro 1-OHase activity was not different from that of rats of the same age fed NCD and infused with vehicle alone (Fig. 2) . In 24-mo-old rats fed LCD and infused with rhIGF-I, 1-OHase activity was ~80% greater than that in rats fed LCD and infused with vehicle (Fig. 2) . The proportional and absolute elevations in 1-OHase activity in 24-mo old rats fed LCD and treated with rhIGF-I were not different than the increase in 1-OHase activity in 1-mo-old rats fed LCD compared with those fed NCD.

View larger version (19K): [in this window] [in a new window]   Figure 2. In vitro 25-hydroxyvitamin D 1--hydroxylase (1-OHase) activity by renal proximal tubules prepared from 1- and 24-mo-old Fischer 344 male rats fed either a normal calcium diet (NCD, 6 g Ca/kg diet) or low calcium diet (LCD, 0.2 g Ca/kg diet) for 14 d. The 24-mo-old rats were infused with either recombinant human insulin growth factor-I (I, rhIGF-I) or vehicle (V) during d 12–14. One-mo-old rats did not receive I or V. Values are means ± SEM from five separate experiments. The 24-mo-old rats were infused with either rhIGF-I [1.4 mg/(24 h·kg body wt)] or vehicle alone for 72 h before killing. Age and diet effects were analyzed using two-way ANOVA and Bonferroni Correction (see Methods). **In 1-mo-old rats, LCD was greater than NCD, P < 0.0001; *in 24-mo-old rats fed LCD and infused with rhIGF-I, 1-OHase was greater than other groups of 24-mo old rats.

LCD did not alter weight gain in either 1- or 24-mo-old rats. The 24-mo-old rats fed LCD and receiving rhIGF-I gained more weight than rats fed NCD and treated with vehicle (Table 3) . Serum calcium, phosphate and glucose were greater in 1-mo-old rats than in 24-mo old rats independent of diet (Table 3 , 1 -mo-old fed NCD and LCD were greater than 24-mo old NCD-V and LCD-V). Neither diet nor rhIGF-I administration altered serum calcium, phosphate or glucose in 24 mo-old rats (Table 3 , NCD-I, NCD-V, LCD-I, LCD-V not different). Serum PTH levels in 1-mo-old rats fed LCD were greater than in those fed NCD (Table 3) . In rats fed NCD, serum PTH levels were higher in 24-mo-old rats than in 1-mo-old rats (P < 0.028). Serum PTH levels tended to be higher in 24-mo-old rats fed LCD, than in those fed NCD (Table 3 , P < 0.14). Serum IGF-I levels were not different in 1-mo-old rats fed NCD or LCD, and there was no difference in serum IGF-I levels between 1- and 24-mo-old rats fed NCD or LCD (Table 3) . Serum IGF-I levels in 24-mo-old rats infused with rhIGF-I were greater than in those infused with vehicle, independent of diet. Serum creatinine was greater in 24-mo-old rats compared with 1-mo-old rats independent of diet Ca and IGF-I administration (P < 0.0002, Table 4 ). Rats fed LCD had serum creatinine concentrations that were comparable to those fed NCD for each age group (Table 4) . Creatinine clearance in 24-mo-old rats was almost 50% lower than that in 1-mo old rats independent of diet Ca and IGF-I administration (P < 0.01, Table 4 ). In 24-mo-old rats, neither IGF-I infusion nor changes in dietary Ca intake (NCD vs. LCD) altered serum creatinine or creatinine clearance (Table 4) .

	DISCUSSION

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Previously, we reported that a low P diet (LPD) increases 1,25(OH)₂D₃ production in 4-mo-old Sprague-Dawley rats only during rhIGF-I infusion at the same dose and duration used in this study (Wong et al. 1997 ). Thus, rhIGF-I administration permits stimulation of 1-OHase activity in response to either LCD or LPD in both mature (4-mo-old) and aged (24-mo-old) rats in which the normal adaptive response to dietary mineral restriction has been lost.

PTH is a major physiologic stimulus of renal 1-OHase activity in young animals. However, old animals fail to respond to either PTH that has been elevated during LCD consumption or after administration of pharmacologic doses (Armbrecht et al. 1982 and 1984 , Friedlander et al. 1994 ). In this study, serum PTH levels were elevated, as expected, in 4- and 24-mo-old rats (Armbrecht et al. 1984 ) to levels found in younger rats fed LCD. Therefore, the lack of increase in 1-OHase in older rats fed LCD was not due to insufficient PTH. PTH regulates a number of renal proximal tubule functions, including inhibition of Na-dependent P transport (Suki and Rouse 1996 ) as well as 1-OHase activity. However, the age-related resistance to PTH is specific for control of 1,25(OH)₂D₃ synthesis because P transport remains sensitive to PTH at a time when 1-OHase stimulation is lost (Armbrecht et al. 1986 ).

The resistance of renal 1-OHase to stimulation by LCD and PTH in mature and old rats has been attributed to an age-related decline in renal function (Meyer 1989 ); therefore, the reduction in 1-OHase was likely to be an irreversible loss. However, the absence of renal 1-OHase response to PTH was reversed by the administration of rhIGF-I in 24-mo-old rats with reduced creatinine clearance (Table 4) . Thus, these studies show that the loss of 1-OHase adaptation to LCD is reversible in old rats despite their reduced renal function.

The mechanism by which PTH stimulation of 1-OHase is lost with advancing age remains unknown, but several possible sites exist in the complex series of events involving intracellular signaling and gene expression. We have found that proximal tubule intracellular signaling via the adenylate cyclase/cAMP/protein kinase A and the diacyl glycerol/protein kinase C pathways remains responsive to PTH in old rats (Friedlander et al. 1994 ). These studies suggest that the defect with advancing age may involve steps distal to plasma membrane and intracytosolic signaling events. In this study, rhIGF-I overcame the resistance to PTH in tubules from rats fed LCD. Although the mechanism by which IGF-I exerts its action has not been investigated, the results showed that rhIGF-I infusion must have reestablished PTH stimulation of the 1-OHase by mechanisms that did not involve an increase in PTH secretion.

In humans, serum IGF-I levels decline with age. However, serum IGF-I levels fall rapidly in rats, so that stable levels are reached within the first weeks of life. This was demonstrated in the Fischer 344 rats, in which serum IGF-I levels were not different between 1 and 24 mo of age. These observations suggest that the decrease in 1-OHase response to PTH with age is not due to a decline in serum IGF-I levels. Infusion of a pharmacologic dose of rhIGF-I increased weight gain in both mature and aged rats fed either LCD or NCD, suggesting that rats at these ages were not resistant to the anabolic actions of IGF-I. Nesbitt and Drezner (1993) found that physiologic doses of rhIGF-I stimulated renal 1-OHase activity in mice fed a normal diet. In this study, larger doses of IGF-I/kg body weight and longer duration of administration led to stimulation of 1-OHase only in mature and old rats fed LCD. These differences may reflect species differences in 1-OHase response to IGF-I, differences in IGF-I binding proteins, metabolism of IGF-I, decrease in intracellular signaling or the required presence of another stimulus, such as PTH, for IGF-I stimulation of 1-OHase in rats.

Previous studies demonstrated that rhIGF-I infusion restored serum 1,25(OH)₂D₃ levels in old rats fed LPD to levels similar to that achieved in young rats fed LPD. In contrast, rhIGF-I infusion to mature and old rats did not further increase serum 1,25(OH)₂D₃ levels during LCD. Because the serum 1,25(OH)₂D₃ level is the balance between synthesis and metabolic clearance, the effect of rhIGF-I on renal 1-OHase activity might not be sufficient to raise serum 1,25(OH)₂D_3. In addition, rhIGF-I might also affect the metabolic clearance of 1,25(OH)₂D₃ during LCD. A recent study by Wei et al. (1998) using the LLC-PK1 cell line demonstrated that IGF-I can increase 24,25(OH)₂D₃ production, suggesting that IGF-I can alter the metabolic clearance of 1,25(OH)₂D₃ by increasing the activity of 25-hydroxyvitamin D-24-hydroxylase (24-OHase).

In summary, the adaptive increase in renal 1,25(OH)₂D₃ production during dietary calcium restriction is lost early in mature rats; rhIGF-I administration restores the increase in 1-OHase activity and serum 1,25(OH)₂D₃ levels at least partially during consumption of a low calcium diet. This study suggests that IGF-I may be important in mediating the 1-OHase adaptation to dietary calcium restriction. Further research is required to understand the mechanism of IGF-I regulation of renal 1-OHase activity during LCD consumption in mature or old rats.

	ACKNOWLEDGMENTS

 
The authors thank Sutin Sriussadaporn for his expert technical advice and assistance and Alexander Karnauskas for his assistance with statistical analyses.

	FOOTNOTES

 
¹ Supported by grant R01 DK 35065 from the National Institutes of Health, Bethesda, MD.

³ Abbreviations used: 1,25(OH)₂D₃, 1,25-dihydroxycholecalciferol; 1-OHase, 25-hydroxyvitamin D 1--hydroxylase; rhIGF-I, recombinant human insulin-like growth factor-I; KHS, Krebs-Hanseleit buffer; LCD, low calcium diet; LPD, low phosphorus diet; NCD, normal calcium diet; PTH, parathyroid hormone.

Manuscript received May 17, 1999. Initial review completed June 21, 1999. Revision accepted January 28, 2000.

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