Role of the Calcium-Sensing Receptor in Reducing the Risk for Calcium Stones

Abstract

SummaryThe tight control of blood Ca 2؉ levels within a narrow range is essential for the performance of vital physiologic functions. Muscle contraction, neuronal excitation, and intracellular signaling processes acquisitively require Ca 2؉ . It is the concerted action of intestine, bone, and kidney that controls the Ca 2؉ balance through the regulation of intestinal absorption, bone (de)mineralization, and renal excretion of Ca 2؉ , respectively. Along the nephron, fine-tuning of blood Ca 2؉ levels takes place by Ca 2؉ reabsorption. The calciotropic hormones regulate Ca 2؉ transport processes, leading to whole-body Ca 2؉ homeostasis and, importantly, preserving a constant Ca 2؉ concentration in the blood. Defects in renal Ca 2؉ handling can lead to hypercalciuria, consecutive kidney stone formation, and obstructive nephropathy. Here we give an overview of the key players involved in normal Ca 2؉ management and describe the in-depth investigations on a renal hypercalciuric model of disease, the Trpv5 knockout mouse, which naturally displays molecular adaptations that prevent Ca 2؉ precipitation in the kidney.

Melamine induces Ca2+-sensing receptor activation and elicits apoptosis in proximal tubular cells

“…Such a process can cause a disturbance in apico-basal [Ca 2ϩ ] i mobilization required for transepithelial Ca 2ϩ transport (4), which we did not explore because of the limited scope of this study. Indeed, such a consequent compromise in Ca 2ϩ clearance attributable to the exposure of melamine from contaminated food could have an implication in noncyanurate stone formation, such as the calcium phosphate/calcium oxalate stones (41). Furthermore, the oxidative stress, lipids, and cell debris are all factors to crystal growth in such noncyanurate kidney stone formation (27).…”

“…This could be involved in the ER mitochondria Ca 2ϩ transfer mechanism (38), activating the mitochondrial cell death pathway. Because we used LLC-PK1 cells, a proximal tubular cell line, we propose that such tubular cell injury and cell death can produce cell debris, which can well be a contributing factor in the downstream process of the growth phase of stone formation (41).…”

Acid-base regulation in the renal proximal tubules: using novel pH sensors to maintain homeostasis

“…In addition, increased NHE3 activity by CaSR acidifies the lumen pH, which has been hypothesized to ionize calcium and favor calcium reabsorption in the distal regions of the nephron. Furthermore, CaSR activation has been shown to block parathyroid hormone-mediated inhibition of phosphate reabsorption, thereby preventing renal Ca 2ϩ -phosphate precipitation and calcium nephrolithiasis (20).…”

Immunolocalization of the calcium-sensing receptor in developing human kidney

“…These observations suggest that urine calcium does not have a clinically significant role in osmoregulation. Diminished expression or responsiveness of the CSR in the CD could play a role in the pathogenesis of nephrocalcinosis, which has been reported to occur in up to 15% of premature infants (22).…”