Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP3 pathway and the ryanodine receptor
M. Cecilia Ortiz-Capisano,Mahendranath Reddy,Mariela Mendez,Jeffrey L. Garvin,Jeffrey L. Garvin,William H. Beierwaltes,William H. Beierwaltes +6 more
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TLDR
In this article, the postreceptor pathway for the CaSR in renal juxtaglomerular (JG) cells is unknown and the authors hypothesized JG cell CaSR activation inhibits renin via the PLC/IP(3) and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release.Abstract:
The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through G(q) and/or G(i). Activation of G(q) stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP(3)), releasing calcium from intracellular stores. G(i) stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP(3) and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells (n = 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 ± 7% of control (P < 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 ± 11% of control). The IP(3) inhibitor 2-APB also reversed inhibition of renin from 56 ± 6 to 104 ± 11% of control (P < 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 ± 8 to 118 ± 22% of control (P < 0.01). Combining inhibition of IP(3) and RyR was not additive. G(i) inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 ± 12 to 41 ± 8% of control, P < 0.001). We conclude stimulating JG cell CaSR activates G(q), initiating the PLC/IP(3) pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition.read more
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Journal ArticleDOI
Localization and function of the renal calcium-sensing receptor
TL;DR: The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner, and the potential impact of pharmacological modulation of the CaSR on renal function is discussed.
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The renin–angiotensin–aldosterone system and calcium-regulatory hormones
TL;DR: The known clinical interactions between the renin–angiotensin–aldosterone system and calcium-regulatory systems are described including observational and interventional studies and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone is reviewed.
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Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.
Jenifer M Brown,Jonathan S. Williams,James M. Luther,Rajesh Garg,Amanda E Garza,Luminita H. Pojoga,Daniel T. Ruan,Gordon H. Williams,Gail K. Adler,Anand Vaidya +9 more
TL;DR: Novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism are observed: the acute modulation of P TH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAas on PTH may involve aldosterone.
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Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney
Joao Graca,Martin Schepelmann,Sarah C. Brennan,Jaimini Reens,Wenhan Chang,Paul Yan,Hakan R. Toka,Daniela Riccardi,Sally A. Price +8 more
TL;DR: CaSR expression is demonstrated throughout the kidney with minimal discrepancy between species but with significant variation in the levels of expression between cell and tubule types, clearing the intrarenal distribution of the CaSR and enabling elucidation of the full physiological roles of the receptor within this organ.
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Dual-Functional Dendritic Mesoporous Bioactive Glass Nanospheres for Calcium Influx-Mediated Specific Tumor Suppression and Controlled Drug Delivery in Vivo
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TL;DR: Dendritic MBG nanospheres with antitumor activity and controlled drug release have been successfully achieved and the underlying molecular mechanism was elucidated, paving the way for translational application.
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Cloning and characterization of an extracellular Ca 2+ -sensing receptor from bovine parathyroid
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Edward M. Brown,R. John MacLeod +1 more
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