Cyclosporine A-induced hypercalciuria in calbindin-D28k knockout and wild-type mice

Lee, Chien Te; Huynh, Viet M.; Lai, Li Wen; Lien, Yeong‐Hau H.

doi:10.1046/j.1523-1755.2002.00670.x

Cited by 64 publications

(48 citation statements)

References 26 publications

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“…We then treated TPTX, PTH-supplemented rats with an antibone-resorptive agent (2.5 μg pamidronate.g BW -1 , daily for 4 days prior to the experiment); this treatment significantly inhibits bone resorption in rats and mice as validated in previous studies (9,12,13). As shown in Figure 4, at baseline, both groups of rats exhibited the same blood ionized Ca concentration and urinary Ca excretion.…”

Section: Figurementioning

confidence: 77%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

181

171

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Tight regulation of calcium levels is required for many critical biological functions. The Ca 2+ -sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

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Section: Figurementioning

confidence: 77%

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Loupy¹,

Ramakrishnan²,

Wootla³

et al. 2012

J. Clin. Invest.

181

171

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“…Some studies show that these genes are regulated by calcium but not 1,25-dihydroxyvitmain D 3 in mice lacking VDR (38), whereas others show that they are modulated by both calcium and 1,25-dihydroxyvitmain D 3 in WT mice (39) and in mice lacking 1␣-hydoxylase (5). A previous report also shows that levels of TRPV5 are not altered in CaBP-D28k(Ϫ/Ϫ) mice (32). Here we demonstrate that expression of both TRPV5 and TRPV6 is not changed in CaBP-D28k(Ϫ/Ϫ) mice but down-regulated by about the same magnitude in both VDR(Ϫ/Ϫ) and double KO mice.…”

Section: Table II Physiological Parameters Of 2-month Old Wt Cabp-d2mentioning

confidence: 83%

“…The bone phenotype, presumably normal, was not investigated when the KO mice were first reported. More recent studies reported that CaBP-D28k(Ϫ/Ϫ) mice fed a 1% calcium diet had higher urinary calcium excretion and a lower bone turnover rate than WT mice, even though their serum calcium levels and intestinal CaBP-D9k expression were normal (31,32). In theory, to maintain a calcium balance, these mutant mice need to have increased intestinal calcium absorption and/or higher bone turnover, which is contradictory to the normal intestinal CaBP-D9k levels and lower bone turnover seen in these mice.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Zheng

Xie

et al. 2004

Journal of Biological Chemistry

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Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5-3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.It is well established that calcium homeostasis is primarily maintained by the vitamin D and parathyroid hormone (PTH) 1 endocrine systems. In this regard, the principal role of vitamin D is to regulate calcium transport in the intestine and kidney. Intestinal and renal distal tubular calcium transfer consists of a passive, concentration gradient-dependent paracellular transport and an active, ATP-dependent transcellular transport (1). The latter is largely regulated by vitamin D and is crucial when calcium supply is low. It is believed that the vitamin D-mediated transcellular calcium transport in the duodenum and renal distal tubules involves three sequential steps: entry, intracellular movement, and extrusion. Influx of luminal calcium into the epithelial cells is propelled by a steep electrochemical gradient across the apical membrane, saturable at high levels of luminal calcium, and mediated by apical calcium channels (2-4). Once in the cytosol, calcium binds to the vitamin D-dependent calcium-binding proteins, calbindins (CaBPs), which ferry calcium from the apical to the basolateral portion of the cell, where the Na ϩ /Ca 2ϩ exchanger and Ca 2ϩ -dependent ATPase on the basolateral membrane extrude calcium into extracellular fluids (5-7). It is believed that the apical to b...

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“…CsA has been previously shown to enable repeated administration of monoclonal antibody therapy in patients by reducing the HAMA response (Ledermann et al, 1988;Weiden et al, 1994). Notably, the amount of CsA administered in the in vivo experiments in rats was lower, based on several publications (Palomero et al, 2001;Lee et al, 2002), that the doses commonly used in patients for immunosupression, as calculated from commonly used guidelines for conversion of doses between different species (www.fda.gov/Cber/ gdlns/dose.htm). However, whether CsA can inhibit the antibody formation to the IT will be studied in a clinical trial in 2009 in our clinical trials unit.…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo

2009

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BACKGROUND: The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human-anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious. METHODS: We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats. RESULTS: The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented. CONCLUSION: The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients.

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Cyclosporine A-induced hypercalciuria in calbindin-D28k knockout and wild-type mice

Cited by 64 publications

References 26 publications

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo

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