Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells.
Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells.
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DOI：
10.1038/s41598-018-23732-5
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发表时间：
2018-04-09
影响因子：
4.6
通讯作者：
Valenti G
中科院分区：
文献类型：
--
作者：
Di Mise A;Tamma G;Ranieri M;Centrone M;van den Heuvel L;Mekahli D;Levtchenko EN;Valenti G
Clinical and fundamental research suggest that altered calcium and cAMP signaling might be the most proximal events in ADPKD pathogenesis. Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca2+]i and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca2+]i increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS-R568 induced a significant increase in [Ca2+]i in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca2+]i were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca2+]i, reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target.
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DOI：
10.1016/j.bbadis.2010.09.016
发表时间：
2011-10
影响因子：
6.2
作者：
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影响因子：
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作者：
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