Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney

Graça, João; Schepelmann, Martin; Brennan, Sarah C.; Reens, Jaimini; Chang, Wenhan; Yan, Paul; Toka, Hakan R.; Riccardi, Daniela; Price, Shirley C.

doi:10.1152/ajprenal.00208.2015

Cited by 56 publications

(62 citation statements)

References 44 publications

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“…In the kidney, CaSR is well-known for regulating calcium secretion and absorption in renal tubules [4]. However, accumulating evidence indicates that CaSR is expressed in glomeruli as well, including mesangial cells and podocytes [5]. Observations from our group and others show that CaSR is expressed in mesangial cells and regulates cell proliferation [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Recent studies provided compelling evidence that stimulation of the calcium sensing receptor (CaSR) exerts direct renoprotective action at the glomerular podocyte level. This protective action may be attributed to the RhoA-dependent stabilization of the actin cytoskeleton. However, the underlying mechanisms remain unclear. Methods: In the present study, an immortalized human podocyte cell line was used. Fluo-3 fluorescence was utilized to determine intracellular Ca²⁺ concentration ([Ca²⁺]_i), and western blotting was used to measure canonical transient receptor potential 6 (TRPC6) protein expression and RhoA activity. Stress fibers were detected by FITC-phalloidin. Results: Activating CaSR with a high extracellular Ca²⁺ concentration ([Ca²⁺]_o) or R-568 (a type II CaSR agonist) induces an increase in the [Ca²⁺]_i in a dose-dependent manner. This increase in [Ca²⁺]_i is phospholipase C (PLC)-dependent and is smaller in the absence of extracellular Ca²⁺ than in the presence of 0.5 mM [Ca²⁺]_o. The CaSR activation-induced [Ca²⁺]_i increase is attenuated by the pharmacological blockage of TRPC6 channels or siRNA targeting TRPC6. These data suggest that TRPC6 is involved in CaSR activation-induced Ca²⁺ influx. Consistent with a previous study, CaSR stimulation results in an increase in RhoA activity. However, the knockdown of TRPC6 significantly abolished the RhoA activity increase induced by CaSR stimulation, suggesting that TRPC6-dependent Ca²⁺ entry is required for RhoA activation. The activated RhoA is involved in the formation of stress fibers and focal adhesions in response to CaSR stimulation because siRNA targeting RhoA attenuated the increase in the stress fiber mediated by CaSR stimulation. Moreover, this effect of CaSR activation on the formation of stress fibers is also abolished by the knockdown of TRPC6. Conclusion: TRPC6 is involved in the regulation of stress fiber formation and focal adhesions via the RhoA pathway in response to CaSR activation. This may explain the direct protective action of CaSR agonists.

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Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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“…CaSR is expressed in various renal cell types in the distal nephron (Graca et al . ). In the present study, the vitamin D/hypercalcaemia‐induced increase in ET‐1 expression was restricted to DCT, CNT and CCD, and none occurred in TAL, despite the much higher expression of CaSR in medullary thick ascending limb and cortical thick ascending limb than in any other tubular segment (Loupy et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Graca et al . ). Moreover, ET‐1 mRNA expression did not significantly differ between mice expressing an activating mutation of Casr and wild‐type mice.…”

Section: Discussionmentioning

confidence: 97%

Endothelin‐1 mediates natriuresis but not polyuria during vitamin D‐induced acute hypercalcaemia

Tokonami

Cheval

Monnay

et al. 2017

The Journal of Physiology

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Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.

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“…In the kidney, CaSR senses changes in both urine and serum calcium levels, which indicates a direct role in renal calcium handling (30). In the collecting duct, CaSR is expressed in intercalated cells and principal cells of the collecting duct (53) and is activated by luminal calcium. Specifically, in principal cells, CaSR is colocalized with the AQP2 water channel (30, 53, 54).…”

Section: Discussionmentioning

confidence: 99%

“…In the collecting duct, CaSR is expressed in intercalated cells and principal cells of the collecting duct (53) and is activated by luminal calcium. Specifically, in principal cells, CaSR is colocalized with the AQP2 water channel (30, 53, 54). Several in vitro and in vivo studies, including those in humans, have suggested that CaSR signaling inhibits vasopressin‐induced trafficking and expression of AQP2 (22, 24‐26, 28, 55‐58).…”

Section: Discussionmentioning

confidence: 99%

CaSR signaling down‐regulates AQP2 expressionviaa novel microRNA pathway in pendrin and NaCl cotransporter knockout mice

et al. 2018

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High concentrations of urinary calcium counteract vasopressin action via the activation of the calcium-sensing receptor (CaSR) that is expressed in the luminal membrane of collecting duct cells, which impairs the trafficking of aquaporin-2 (AQP2). Pendrin/NaCl cotransporter double-knockout (dKO) mice display significant calcium wasting and develop severe volume depletion, despite increased circulating vasopressin levels. We hypothesized that the CaSR-mediated impairment of AQP2 expression/trafficking underlies vasopressin resistance in dKO mice. Compared with wild-type mice, in renal inner medulla, dKO mice had reduced total AQP2 sensitive to proteasome inhibitors, higher levels of AQP2-pS261, ubiquitinated AQP2, and p38-MAPK, an enzyme that is activated by CaSR signaling and known to phosphorylate AQP2 at Ser261. CaSR inhibition with the calcilytic NPS2143 reversed these effects, which indicates that CaSR mediates the up-regulation of AQP2-pS261, ubiquitination, and degradation. Of note, dKO mice demonstrated significantly higher AQP2-targeting miRNA-137 that was reduced upon CaSR inhibition, supporting a critical role for CaSR in the down-regulation of AQP2 expression. Our data indicate that CaSR signaling reduces AQP2 abundance both via AQP2-targeting miRNA-137 and the p38-MAPK/AQP2-pS261/ubiquitination/proteasomal axis. These effects may contribute to the reduced renal concentrating ability that has been observed in dKO mice and underscore a physiologic mechanism of the CaSR-dependent regulation of AQP2 abundance via a novel microRNA pathway.-Ranieri, M., Zahedi, K., Tamma, G., Centrone, M., Di Mise, A., Soleimani, M., Valenti, G. CaSR signaling down-regulates AQP2 expression via a novel microRNA pathway in pendrin and NaCl cotransporter knockout mice.

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Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney

Cited by 56 publications

References 44 publications

Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation

Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation

Endothelin‐1 mediates natriuresis but not polyuria during vitamin D‐induced acute hypercalcaemia

CaSR signaling down‐regulates AQP2 expressionviaa novel microRNA pathway in pendrin and NaCl cotransporter knockout mice

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