There is certainly an enormous consensus away from CaSR phrase on basolateral membrane layer of your TAL (118, 143, 166), however, the precise part might have been just has just elucidated. Really elegant and you can done analysis, Loupy ainsi que al. (118) revealed that CaSR generally controls the brand new paracellular calcium supplements-reabsorbing pathways by a however challenging method and most likely quicker so NKCC2, compared with earlier in the day opinions. In the vitro research has suggested you to definitely CaSR controls the newest claudin- complex, including claudin-14: claudin-sixteen phosphorylation is actually reduced and you can cellular localization altered upon CaSR activation when you look at the cells (86)], and CLDN14 transcript profile was basically improved within echar un vistazo a este enlace the rats treated with a beneficial CaSR agonist (43). Correctly, mice having kidney-particular ablation of your CaSR gene showed downregulated CLDN14 and you will upregulated CLDN16 phrase (193). Over the same range, it had been observed one to miRNA control away from CLDN14 mRNA try regulated by the CaSR (59, 60). In conclusion, the CaSR from the TAL inhibits passive calcium reabsorption mediated from the new paracellular claudin network.
The significance of the CaSR to possess kidney calcium dealing with in the human beings might have been in addition to backed by several genome-large organization studies getting gel calcium supplements having located several common CaSR versions influencing calcium account (89, 143, 144). Population-established studies relevant the CaSR gene in addition to that have urinary calcium supplements (88) and you can nephrolithiasis (176, 201).
Reflect monogenic sickness show the significance of CaSR having calcium homeostasis. Similarly, familial hypocalciuric hypercalcemia (FHH) comes from loss-of-mode mutation of your CaSR (126). This disease was initially thought to be an enthusiastic autosomal-dominating infection of parathyroid gland, the spot where the calcium supplements-feeling processes is changed and contributes to highest plasma number of calcium and you may unsuppressed PTH (52). It actually was called familial safe hypercalcemia. Although not, some instances out-of neonatal serious first hyperparathyroidism (127) have achieved distinct desire and was basically afterwards shown to be the latest homozygous sorts of FHH (157). During the 1993, the underlying unit problem try recognized as a great missense mutation inside the the fresh new CaSR (155). Additionally, triggering missense mutations of CaSR had been defined as the reason out-of autosomal dominant hypocalcemia having hypercalciuria (82, 149, 156, 158).
Yet not, the relationship amongst the CaSR and you may supplement D is more difficult: this new CaSR generally seems to dampen vitamin D’s effects into the calcium reabsorption (48)
The CaSR is linked to other regulatory pathways of calcium homeostasis, such as 1,25(OH)2-vitamin D (1) or PTH (112, 199). While Toka et al. (193) had already proposed a PTH-independent action of the CaSR in mice with kidney-specific deletion of the CaSR gene that displayed hypocalciuria, further evidence was established by Loupy et al. (118), who clamped calcium-dependent PTH secretion in rats by performing thyroparathyroidectomy and continuous PTH replacement for their experiments. This approach allowed a precise dissection of the role of renal CaSR independently from systemic influences of PTH. It stressed the importance of renal CaSR-dependent calcium reabsorption for the whole calcium homeostasis.
CaSR might be in person modulated by the agonists such as for instance cinacalcet (43, 153) or because of the antagonists and you may causes respectively hyper- and you may hypocalciuria. Away from note, calcimimetics have been used to fix the outcome regarding inactivating CaSR mutations (119, 169).
Calcium transport regarding TAL is additionally consuming calcitropic hormone. On the cortical part of the TAL, calcium reabsorption try sparked of the PTH (21, 22), even alone from transepithelial voltage (118). Although not, the specific aftereffect of PTH towards the transepithelial current regarding TAL remains unclear (209).
The role of vitamin D on TAL-mediated calcium reabsorption is not well established. 2-vitamin D and rendered hypercalcemic, a decreased expression of NKCC2 and ROMK has been observed, explaining the polyuria associated with hypercalcemia (203). Vitamin D was also shown to increase CaSR expression in the kidney (1).