| First Author | Shumilina E | Year | 2013 |
| Journal | Am J Physiol Cell Physiol | Volume | 305 |
| Issue | 1 | Pages | C70-7 |
| PubMed ID | 23596175 | Mgi Jnum | J:202790 |
| Mgi Id | MGI:5521450 | Doi | 10.1152/ajpcell.00355.2012 |
| Citation | Shumilina E, et al. (2013) Altered regulation of cytosolic Ca(2)(+) concentration in dendritic cells from klotho hypomorphic mice. Am J Physiol Cell Physiol 305(1):C70-7 |
| abstractText | The function of dendritic cells (DCs), antigen-presenting cells regulating naive T-cells, is regulated by cytosolic Ca(2)(+) concentration ([Ca(2)(+)]i). [Ca(2)(+)]i is increased by store-operated Ca(2)(+) entry and decreased by K(+)-independent (NCX) and K(+)-dependent (NCKX) Na(+)/Ca(2)(+) exchangers. NCKX exchangers are stimulated by immunosuppressive 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)], the biologically active form of vitamin D. Formation of 1,25(OH)(2)D(3) is inhibited by the antiaging protein Klotho. Thus 1,25(OH)(2)D(3) plasma levels are excessive in Klotho-deficient mice (klothohm). The present study explored whether Klotho deficiency modifies [Ca(2)(+)]i regulation in DCs. DCs were isolated from the bone marrow of klothohm mice and wild-type mice (klotho+/+) and cultured for 7-9 days with granulocyte-macrophage colony-stimulating factor. According to major histocompatibility complex II (MHC II) and CD86 expression, differentiation and lipopolysaccharide (LPS)-induced maturation were similar in klothohm DCs and klotho+/+ DCs. However, NCKX1 membrane abundance and NCX/NCKX-activity were significantly enhanced in klothohm DCs. The [Ca(2)(+)]i increase upon acute application of LPS (1 mug/ml) was significantly lower in klothohm DCs than in klotho+/+ DCs, a difference reversed by the NCKX blocker 3',4'-dichlorobenzamyl (DBZ; 10 muM). CCL21-dependent migration was significantly less in klothohm DCs than in klotho+/+ DCs but could be restored by DBZ. NCKX activity was enhanced by pretreatment of klotho+/+ DC precursors with 1,25(OH)(2)D(3) the first 2 days after isolation from bone marrow. Feeding klothohm mice a vitamin D-deficient diet decreased NCKX activity, augmented LPS-induced increase of [Ca(2)(+)]i, and enhanced migration of klothohm DCs, thus dissipating the differences between klothohm DCs and klotho+/+ DCs. In conclusion, Klotho deficiency upregulates NCKX1 membrane abundance and Na(+)/Ca(2)(+)-exchange activity, thus blunting the increase of [Ca(2)(+)]i following LPS exposure and CCL21-mediated migration. The effects are in large part due to excessive 1,25(OH)(2)D(3) formation. |
