Abstract
One mechanism proposed for reducing the risk of calcium renal stones is activation of the calcium-sensing receptor (CaR) on the apical membranes of collecting duct principal cells by high luminal calcium. This would reduce the abundance of aquaporin-2 (AQP2) and in turn the rate of water reabsorption. While evidence in cells and in hypercalciuric animal models supports this hypothesis, the relevance of the interplay between the CaR and AQP2 in humans is not clear. This paper reports for the first time a detailed correlation between urinary AQP2 excretion under acute vasopressin action (DDAVP treatment) in hypercalciuric subjects and in parallel analyzes AQP2-CaR crosstalk in a mouse collecting duct cell line (MCD4) expressing endogenous and functional CaR. In normocalciurics, DDAVP administration resulted in a significant increase in AQP2 excretion paralleled by an increase in urinary osmolality indicating a physiological response to DDAVP. In contrast, in hypercalciurics, baseline AQP2 excretion was high and did not significantly increase after DDAVP. Moreover DDAVP treatment was accompanied by a less pronounced increase in urinary osmolality. These data indicate reduced urinary concentrating ability in response to vasopressin in hypercalciurics. Consistent with these results, biotinylation experiments in MCD4 cells revealed that membrane AQP2 expression in unstimulated cells exposed to CaR agonists was higher than in control cells and did not increase significantly in response to short term exposure to forskolin (FK). Interestingly, we found that CaR activation by specific agonists reduced the increase in cAMP and prevented any reduction in Rho activity in response to FK, two crucial pathways for AQP2 translocation. These data support the hypothesis that CaR–AQP2 interplay represents an internal renal defense to mitigate the effects of hypercalciuria on the risk of calcium precipitation during antidiuresis. This mechanism and possibly reduced medulla tonicity may explain the lower concentrating ability observed in hypercalciuric patients.
Highlights
The incidence of renal calcium stones has risen steadily over the past 30 years to become the main cause of hospitalization for uronephrologic reasons [1]
Electrolytes, urine osmolality and AQP2 excretion evaluations in hypercalciuric patients subjected to the DDAVP test 24 h urine flow rate were measured in patients with a past history of hypercalciuria that was defined by a urinary Ca/creat ratio .0.2 mg/mg on 3 separate samples obtained during a 24 h period and had been investigated after presenting with hematuria or nephrolithiasis at the ‘‘Bambino Gesu’’ Pediatric Hospital in Rome, Italy
Patients were reclassified as hypercalciuric (n = 21) or normocalciuric (n = 32) based on their urinary calcium excretion measured on samples obtained during the DDAVP test
Summary
The incidence of renal calcium stones has risen steadily over the past 30 years to become the main cause of hospitalization for uronephrologic reasons [1]. Urinary saturation may be the most important factor in stone pathogenesis and is strictly correlated to water reabsorption in the kidney. The kidney is a key organ regulating both water and calcium homeostasis, and its ability to sense extracellular calcium levels in both the urinary filtrate and the interstitial fluid is due to the extracellular Calcium–Sensing Receptor (CaR), which is expressed in multiple sites along the nephron [4]. The apically located CaR in the proximal tubules appears to directly attenuate parathyroid hormone (PTH)-induced inhibition of phosphate reabsorption by proximal tubules and inhibits PTHdependent phosphate uptake. Activation of distal tubular CaR, which is located basolaterally, directly inhibits tubular calcium and magnesium reabsorption. In addition to indirectly increasing renal calcium excretion as a result of lowering PTH levels, directly promotes calciuria
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