Calcium transport across segments of the rabbit distal nephron in vitro

Shareghi, G. R.; Stoner, L. C.

doi:10.1152/ajprenal.1978.235.4.f367

Cited by 88 publications

(65 citation statements)

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“…11,18,34,35 Use of the adenylyl cyclase-activating compound, forskolin, and cell-permeable cAMP analogs in ex vivo models of active Ca 2ϩ reabsorption mimicked the stimulatory effect of PTH. 11,17,19,20,36,37 Several studies suggested that PTH positively influences the uptake of Ca 2ϩ from the pro-urine, although the specific protein mediating the apical influx of Ca 2ϩ was unknown. 5,17,18 In 1999, Hoenderop et al 38 identified TRPV5 as the apical uptake mechanism for active Ca 2ϩ reabsorption in DCT and CNT.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Activates TRPV5 via PKA-Dependent Phosphorylation

Groot

Lee²,

Langeslag³

et al. 2009

Journal of the American Society of Nephrology

148

103

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Low extracellular calcium (Ca 2ϩ ) promotes release of parathyroid hormone (PTH), which acts on multiple organs to maintain overall Ca 2ϩ balance. In the distal part of the nephron, PTH stimulates active Ca 2ϩ reabsorption via the adenylyl cyclase-cAMP-protein kinase A (PKA) pathway, but the molecular target of this pathway is unknown. The transient receptor potential vanilloid 5 (TRPV5) channel constitutes the luminal gate for Ca 2ϩ entry in the distal convoluted tubule and has several putative PKA phosphorylation sites. Here, we investigated the effect of PTH-induced cAMP signaling on TRPV5 activity. Using fluorescence resonance energy transfer, we studied cAMP and Ca 2ϩ dynamics during PTH stimulation of HEK293 cells that coexpressed the PTH receptor and TRPV5. PTH increased cAMP levels, followed by a rise in TRPV5-mediated Ca 2ϩ influx. PTH (1 to 31) and forskolin, which activate the cAMP pathway, mimicked the stimulation of TRPV5 activity. Remarkably, TRPV5 activation was limited to conditions of strong intracellular Ca 2ϩ buffering. Cell surface biotinylation studies demonstrated that forskolin did not affect TRPV5 expression on the cell surface, suggesting that it alters the single-channel activity of a fixed number of TRPV5 channels. Application of the PKA catalytic subunit, which phosphorylated TRPV5, directly increased TRPV5 channel open probability. Alanine substitution of threonine-709 abolished both in vitro phosphorylation and PTH-mediated stimulation of TRPV5. In summary, PTH activates the cAMP-PKA signaling cascade, which rapidly phosphorylates threonine-709 of TRPV5, increasing the channel's open probability and promoting Ca 2ϩ reabsorption in the distal nephron.

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Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Activates TRPV5 via PKA-Dependent Phosphorylation

Groot

Lee²,

Langeslag³

et al. 2009

Journal of the American Society of Nephrology

148

103

View full text Add to dashboard Cite

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“…Corresponding to these anatomical features, the rate of sodium transport appears to be quite different between the CNT and the CCD. Measurement of sodium fluxes in isolated rabbit CNTs (43,44) or from rabbit CCDs (45) or rat CCDs (46) indicates at least a 10-fold difference (120-600 pmol versus 0.2-24 pmol of sodium per minute per millimeter in CCD). The rates of sodium transport in OMCD and IMCD are generally low (47) but have been measured only in rabbits (8 versus 1 pmol per minute per millimeter, respectively).…”

Section: Role Of Late Dct and Cnt: The Sodium Transport Capacity Of Tmentioning

confidence: 99%

Collecting duct–specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance

Rubera¹,

Loffing²,

Palmer³

et al. 2003

J. Clin. Invest.

106

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Aldosterone controls the final sodium reabsorption and potassium secretion in the kidney by regulating the activity of the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). ASDN consists of the last portion of the distal convoluted tubule (late DCT), the connecting tubule (CNT), and the collecting duct (CD) (i.e., the cortical CD [CCD] and the medullary CD [MCD]). It has been proposed that the control of sodium transport in the CCD is essential for achieving sodium and potassium balance. We have tested this hypothesis by inactivating the α subunit of ENaC in the CD but leaving ENaC expression in the late DCT and CNT intact. Under salt restriction or under aldosterone infusion, whole-cell voltage clamp of principal cells of CCD showed no detectable ENaC activity, whereas large amiloride-sensitive currents were observed in control littermates. The animals survive well and are able to maintain sodium and potassium balance, even when challenged by salt restriction, water deprivation, or potassium loading. We conclude that the expression of ENaC in the CD is not a prerequisite for achieving sodium and potassium balance in mice. This stresses the importance of more proximal nephron segments (late DCT/CNT) to achieve sodium and potassium balance. Isabelle Rubera, Johannes Loffing, and Edith Hummler contributed equally to this work. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: epithelial sodium channel (ENaC); aldosterone-sensitive distal nephron (ASDN); distal convoluted tubule (DCT); connecting tubule (CNT); collecting duct (CD); cortical CD (CCD); medullary CD (MCD); outer MCD (OMCD); inner MCD (IMCD); adrenalectomized (adx); glomerular filtration rate (GFR); pseudohypoaldosteronism type 1 (PHA-1); X-galactosidase (X-gal); aquaporin-2 (AQP2); sodium/calcium exchanger (NCX); calbindin D28K (CB); sodium thiazide-sensitive chloride cotransporter (NCC).

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“…This may, in part, be related to the greatly increased renal calcium and magnesium loss suffered by the diabetic mother, as compared with her non-diabetic pregnant counterparts [16]; an effect that could influence fetal renal function. Active transcellular calcium transport in the kidney occurs mainly in the distal portion of the nephron [17] and involves three key proteins: epithelial calcium channel 1 (ECaC1), cal-bindin-D 28K and plasma membrane calcium ATPase (PMCA) [18][19][20]. Altered PMCA [20] and calbindin-D 28K [21] expression has been observed in diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

Diabetes in rat pregnancy alters renal calcium and magnesium reabsorption and bone formation in adult offspring

et al. 2005

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Aims/hypothesis: We tested the hypothesis that diabetes in pregnancy can result in the in-utero reprogramming of renal calcium and magnesium handling and of bone formation in the offspring, which persists into adulthood. Methods: Male offspring of streptozotocintreated diabetic rats (OD rats) and of control non-diabetic animals (OC rats) were investigated as neonates and at 8, 12 and 16 weeks of age. Results: Compared with OC rats, urinary calcium and magnesium output was significantly reduced in OD rats at every age studied; Na + and K + outputs were unaffected. The renal expression of proteins involved in the tubular reabsorption of calcium (calcium ATPase, calbindin-D 28k and epithelial calcium channel) was increased in OD animals compared with that in OC animals. Additionally, we observed that adult OD rats had lower trabecular and higher cortical femoral bone volumes, explained by deposition of bone on the endosteal surface. Conclusions/interpretation: These data show that diabetes in pregnancy has profound effects on male offspring in terms of renal tubular calcium and magnesium reabsorption and the normal pattern of bone formation. These effects persist into adulthood. Such long-lasting effects of diabetes on kidney and the skeleton were not suspected and could have important implications for the health of children born to diabetic women.

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Calcium transport across segments of the rabbit distal nephron in vitro

Cited by 88 publications

References 0 publications

Parathyroid Hormone Activates TRPV5 via PKA-Dependent Phosphorylation

Parathyroid Hormone Activates TRPV5 via PKA-Dependent Phosphorylation

Collecting duct–specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance

Diabetes in rat pregnancy alters renal calcium and magnesium reabsorption and bone formation in adult offspring

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