Abstract
Diabetic pregnancy has a marked influence on offspring calcium and magnesium homeostasis. Urinary excretion of calcium and magnesium is reduced, yet offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia. The aim of this study was to measure renal hemodynamic and tubular function in the offspring of diabetic (OD) and control, nondiabetic (OC) rats at 4 and 8 wk of age to determine the glomerular and tubular mechanisms through which renal calcium and magnesium handling are programmed in utero. The fraction of filtered calcium that was excreted was significantly lower in OD at both 4 and 8 wk of age [8 wk: OC (n = 6), 11.8 ± 2.9 versus OD (n = 5), 4.3 ± 0.6%; p < 0.05] and that of magnesium was lower at 8 wk of age [OC (n = 6), 42.4 ± 7.5 versus OD (n = 5), 13.0 ± 1.7%; p < 0.01]. This increased reabsorption occurred despite an elevated GFR in OD. These findings clearly indicate that tubular reabsorptive mechanisms for calcium and magnesium are increased markedly in OD. Serum PTH concentration was reduced in 8-wk-old OD [OC (n = 7), 539.4 ± 142.1 versus OD (n = 9), 174.3 ± 69.4 pg/ml; p < 0.05], consistent with previous reports in human infants. Taken together, these observations suggest that the basis for the altered renal magnesium and calcium handling in OD involves increased tubular transport activity and possibly increased sensitivity of these mechanisms to PTH.
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Abbreviations
- M6PR:
-
IGF-II/mannose-6-phosphate receptor
- OC:
-
offspring of control pregnancy
- OD:
-
offspring of diabetic pregnancy
- PMCA:
-
plasma membrane Ca2+-ATPase pump
- STZ:
-
streptozotocin
- UV:
-
urine flow rate
References
Cruikshank DP, Pitkin RM, Reynolds WA, Williams GA, Hargis GK 1980 Altered maternal calcium homeostasis in diabetic pregnancy. J Clin Endocrinol Metab 50: 264–267
Cruikshank DP, Pitkin RM, Varner MW, Williams GA, Hargis GK 1983 Calcium metabolism in diabetic mother, fetus, and newborn infant. Am J Obstet Gynecol 145: 1010–1016
Mimouni F, Tsang RC, Hertzberg VS, Neumann V, Ellis K 1989 Parathyroid hormone and calcitriol changes in normal and insulin-dependent diabetic pregnancies. Obstet Gynecol 74: 49–54
Verhaeghe J, Bouillon R, Nyomba BL, Lissens W, Van Assche FA 1986 Vitamin D and bone mineral homeostasis during pregnancy in the diabetic BB rat. Endocrinology 118: 1019–1025
Birdsey TJ, Husain SM, Garland HO, Sibley CP 1995 The effect of diabetes mellitus on urinary calcium excretion in pregnant rats and their offspring. J Endocrinol 145: 11–18
Husain SM, Birdsey TJ, Glazier JD, Mughal MZ, Garland HO, Sibley CP 1994 Effect of diabetes mellitus on maternofetal flux of calcium and magnesium and calbindin9K mRNA expression in rat placenta. Pediatr Res 35: 376–381
Tsang RC, Strub R, Brown DR, Steichen J, Hartman C, Chen IW 1976 Hypomagnesemia in infants of diabetic mothers: perinatal studies. J Pediatr 89: 115–119
Tsang RC, Kleinman LI, Sutherland JM, Light IJ 1972 Hypocalcemia in infants of diabetic mothers. Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness. J Pediatr 80: 384–395
Mimouni F, Tsang RC, Hertzberg VS, Miodovnik M 1986 Polycythemia, hypomagnesemia, and hypocalcemia in infants of diabetic mothers. Am J Dis Child 140: 798–800
Bond H, Hamilton K, Glazier J, Sibley CP, Balment RJ 2002 Renal calcium homeostasis, calbindin-D28K and plasma calcium ATPase (PMCA) expression in the offspring of diabetic rats. J Physiol 544P: 94P
Soler NG, Walsh CH, Malins JM 1976 Congenital malformations in infants of diabetic mothers. Q J Med 45: 303–313
Mimouni F, Steichen JJ, Tsang RC, Hertzberg V, Miodovnik M 1988 Decreased bone mineral content in infants of diabetic mothers. Am J Perinatol 5: 339–343
Mishima N, Sahara N, Shirakawa M, Ozawa H 2002 Effect of streptozotocin-induced diabetes mellitus on alveolar bone deposition in the rat. Arch Oral Biol 47: 843–849
Braddock R, Siman CM, Hamilton K, Garland HO, Sibley CP 2002 Gamma-linoleic acid and ascorbate improves skeletal ossification in offspring of diabetic rats. Pediatr Res 51: 647–652
Bond H, Balment RJ, Freemont A, Glazier J, Hamilton K, Sibley CP 2003 Altered renal calcium homeostasis and bone formation in the adult offspring of diabetic rats. Pediatr Res 53( suppl): 27A
Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ 1999 Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274: 8375–8378
Borke JL, Caride A, Verma AK, Penniston JT, Kumar R 1989 Plasma membrane calcium pump and 28-kDa calcium binding protein in cells of rat kidney distal tubules. Am J Physiol 257: F842–F849
Lehotsky J, Kaplan P, Murin R, Raeymaekers L 2002 The role of plasma membrane Ca2+ pumps (PMCAs) in pathologies of mammalian cells. Front Biosci 7: d53–d84
Bergman L, Kjellmer I, Selstam U 1974 Calcitonin and parathyroid hormone—relation to early neonatal hypocalcemia in infants of diabetic mothers. Biol Neonate 24: 151–160
Schedewie HK, Odell WD, Fisher DA, Krutzik SR, Dodge M, Cousins L, Fiser WP 1979 Parathormone and perinatal calcium homeostasis. Pediatr Res 13: 1–6
Ahmed MH, Ashton N, Balment RJ 2003 The effect of chloroquine on renal function and vasopressin secretion: a nitric oxide-dependent effect. J Pharmacol Exp Ther 304: 156–161
Burgess WJ, Shalmi M, Petersen JS, Plange-Rhule J, Balment RJ, Atherton JC 1993 A novel computer-driven, servo-controlled fluid replacement technique and its application to renal function studies in conscious rats. Clin Sci (Lond) 85: 129–137
Hamilton K, Tein M, Glazier J, Mawer EB, Berry JL, Balment RJ, Boyd RD, Garland HO, Sibley CP 2000 Altered calbindin mRNA expression and calcium regulating hormones in rat diabetic pregnancy. J Endocrinol 164: 67–76
Mughal MZ, Eelloo J, Sibartie S, Roberts SA, Maresh M, Sibley CP, Adams JE 2003 Intrauterine programming of urinary calcium and magnesium excretion in children born to mothers with insulin dependent diabetes mellitus. J Bone Miner Res 18( suppl): S172
Ward DT, Yau SK, Mee AP, Mawer EB, Miller CA, Garland HO, Riccardi D 2001 Functional, molecular, and biochemical characterization of streptozotocin-induced diabetes. J Am Soc Nephrol 12: 779–790
Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V 2001 Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 107: 217–224
Schwartz IF, Iaina A, Benedict Y, Wollman Y, Chernichovski T, Brasowski E, Misonzhnik F, Ben-Dor A, Blum M, Levo Y, Schwartz D 2004 Augmented arginine uptake, through modulation of cationic amino acid transporter-1, increases GFR in diabetic rats. Kidney Int 65: 1311–1319
Ito A, Uriu K, Inada Y, Qie YL, Takagi I, Ikeda M, Hashimoto O, Suzuka K, Eto S, Tanaka Y, Kaizu K 2001 Inhibition of neuronal nitric oxide synthase ameliorates renal hyperfiltration in streptozotocin-induced diabetic rat. J Lab Clin Med 138: 177–185
Luippold G, Beilharz M, Muhlbauer B 2004 Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 19: 342–347
Friedman PA 2000 Mechanisms of renal calcium transport. Exp Nephrol 8: 343–350
Bronner F, Stein WD 1988 CaBPr facilitates intracellular diffusion for Ca pumping in distal convoluted tubule. Am J Physiol 255: F558–F562
Uriu-Hare JY, Stern JS, Reaven GM, Keen CL 1985 The effect of maternal diabetes on trace element status and fetal development in the rat. Diabetes 34: 1031–1040
Verhaeghe J, Thomasset M, Brehier A, Van Assche FA, Bouillon R 1988 1,25(OH)2D3 and Ca-binding protein in fetal rats: relationship to the maternal vitamin D status. Am J Physiol 254: E505–E512
Glazier JD, Atkinson DE, Thornburg KL, Sharpe PT, Edwards D, Boyd RD, Sibley CP 1992 Gestational changes in Ca2+ transport across rat placenta and mRNA for calbindin9K and Ca2+-ATPase. Am J Physiol 263: R930–R935
Holemans K, Van Bree R, Verhaeghe J, Meurrens K, Van Assche FA 1997 Maternal semistarvation and streptozotocin-diabetes in rats have different effects on the in vivo glucose uptake by peripheral tissues in their female adult offspring. J Nutr 127: 1371–1376
Amri K, Freund N, Vilar J, Merlet-Benichou C, Lelievre-Pegorier M 1999 Adverse effects of hyperglycemia on kidney development in rats: in vivo and in vitro studies. Diabetes 48: 2240–2245
Amri K, Freund N, Van Huyen JP, Merlet-Benichou C, Lelievre-Pegorier M 2001 Altered nephrogenesis due to maternal diabetes is associated with increased expression of IGF-II/mannose-6-phosphate receptor in the fetal kidney. Diabetes 50: 1069–1075
Hammerman MR 1995 Growth factors in renal development. Semin Nephrol 15: 291–299
Braulke T 1999 Type-2 IGF receptor: a multi-ligand binding protein. Horm Metab Res 31: 242–246
Duong Van Huyen JP, Amri K, Belair MF, Vilar J, Merlet-Benichou C, Bruneval P, Lelievre-Pegorier M 2003 Spatiotemporal distribution of insulin-like growth factor receptors during nephrogenesis in fetuses from normal and diabetic rats. Cell Tissue Res 314: 367–379
Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA 2001 Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81: 51–84
Gunther T 1993 Mechanisms and regulation of Mg2+ efflux and Mg2+ influx. Miner Electrolyte Metab 19: 259–265
Flatman PW 1984 Magnesium transport across cell membranes. J Membr Biol 80: 1–14
Quamme GA 1981 Effect of furosemide on calcium and magnesium transport in the rat nephron. Am J Physiol 241: F340–F347
Mimouni F, Miodovnik M, Tsang RC, Holroyde J, Dignan PS, Siddiqi TA 1987 Decreased maternal serum magnesium concentration and adverse fetal outcome in insulin-dependent diabetic women. Obstet Gynecol 70: 85–88
Mimouni F, Miodovnik M, Tsang RC, Callahan J, Shaul P 1987 Decreased amniotic fluid magnesium concentration in diabetic pregnancy. Obstet Gynecol 69: 12–14
Loughead JL, Mimouni F, Tsang RC, Khoury JC 1991 A role for magnesium in neonatal parathyroid gland function?. J Am Coll Nutr 10: 123–126
de Rouffignac C, Quamme G 1994 Renal magnesium handling and its hormonal control. Physiol Rev 74: 305–322
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This study was funded by the North West Kidney Research Association.
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Bond, H., Sibley, C., Balment, R. et al. Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy. Pediatr Res 57, 890–895 (2005). https://doi.org/10.1203/01.PDR.0000157720.50808.97
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DOI: https://doi.org/10.1203/01.PDR.0000157720.50808.97


