Urinary sodium and calcium excretion: via endothelin‐1 do they part?

Sodium ingestion and urinary sodium excretion is tightly coupled to urinary calcium excretion. This is highlighted by the calciuric effect of most diuretics. Perhaps less appreciated is the tight coupling between plasma calcium concentration and both urinary calcium and sodium excretion. Elegant work from more than half a century ago showed in both man and monkeys that raising serum calcium increases urinary sodium excretion and lowering serum calcium decreases urinary sodium excretion (Levitt et al. 1958). A body of work has pointed to these acute perturbations in plasma calcium levels altering sodium absorption from the thick ascending limb (TAL), thereby altering urinary sodium excretion. Polyuria and polydipsia are two of the fundamental symptoms of hypercalcaemia, but natriuresis is also associated with this electrolyte disorder. Although rare, hypercalcaemia can be life threatening. It is caused by a variety of disease processes including hyperparathyroidism, malignancy and hypervitaminosis D. Unfortunately the natriuresis driven by hypercalcaemia causes volume contraction. This actually makes the hypercalcaemia worse, as volume contraction increases sodium and consequently calcium reabsorption from the proximal nephron, leading to a vicious cycle. The ability to prevent sodium loss in this condition would therefore be clinically beneficial. The molecular details linking increased plasma calcium concentration to increased urinary volume and sodium excretion have been infrequently studied. In this issue of The Journal of Physiology, Tokonami et al. provide molecular insight into this link (Tokonami et al. 2017). The authors employed a more chronic model of hypercalcaemia, the administration of dihydrotachysterol (DHT, a vitamin D analogue) to mice that were Parathyroid hormone (PTH) clamped. They observed that this causes polyuria and increases urinary sodium excretion as others have. Based on previous work demonstrating increased renal endothelin-1 (ET-1) expression in this model of hypercalcaemia, they hypothesized that ET-1 might mediate the natriuric and polyuric effects. ET-1 is known to inhibit the epithelial sodium channel, ENaC. To test their hypothesis they treated mice made hypercalcaemic by administration of DHT in the presence of a PTH clamp with the ETA/ETB inhibitor macitentan. While this had no effect on the development of hypercalcaemia or polyuria, it prevented the increase in urinary sodium excretion, i.e. separating urinary sodium from calcium excretion. The authors extended their experimentation to define the tubular segment failing to reabsorb sodium. To this end, they examined the effects of diuretics on sodium excretion in the various experimental conditions. Surprisingly furosemide increased urinary sodium excretion to the same extent in the controls as in the experimental hypercalcaemia model, suggesting that impaired NaCl reabsorption from the TAL was not the cause of the increased urinary sodium excretion. However, administration of amiloride, a diuretic that blocks ENaC and consequently sodium reabsorption from the collecting duct, attenuated the increase in urinary sodium excretion to the same extent as the ETA/ETB antagonist. This strongly indicates that reduced sodium absorption via ENaC occurs in response to ET-1 signalling in this hypercalcaemic model. A further surprise was that transgenic mice expressing an activating mutation in the calcium-sensing receptor (CaSR) did not have increased ET-1 expression. Further, cell culture work pointed to DHT, and not increased calcium, being responsible for increased ET-1 expression. Previous studies have concluded that the natriuretic response to hypercalcaemia is mediated by reduced NaCl transport from the TAL (Goldfarb & Agus, 1984; Peterson, 1990). Micro stop flow studies on rats made hypercalcaemic by DHT administration observed increased sodium concentration emerging from the loop of Henle (Peterson, 1990). Moreover, application of the same hypercalciuric model to rats for a longer period of time resulted in decreased expression of the major TAL transcellular sodium transporter, NKCC2, inferring a defect in sodium reabsorption from this segment (Wang et al. 2002). Although, in the latter study a functional assessment of TAL sodium absorption was not made and it should be emphasized that changes in expression do not necessarily reflect alterations in transporter/channel activity. Examination of the different experimental approaches is enlightening. The current work is consistent with previous studies from the Houillier group demonstrating that cortical Thick Ascending Limb (cTAL) calcium sensing receptor (CaSR) activation alters calcium flux but not sodium (Loupy et al. 2012). This raises the possibility, given Peterson's findings, that the medullary Thick Ascending Limb (mTAL) and/or thin ascending limb, displays altered sodium reabsorption in response to elevated plasma calcium levels. Further, it should be considered that chronic models of hypercalcaemia and hypercalciuria probably cause intrarenal calcifications and inflammation, perhaps to varying degrees based on duration and the species studied, leading to variable prostaglandin release, which in turn could alter distal nephron sodium absorption. Ultimately this work lends itself to the consideration of a new therapeutic approach to the treatment of hypercalcaemia, which has traditionally initially consisted of volume expansion with saline, and the consideration of a loop diuretic. As mentioned above, natriuresis will drive calciuria hopefully lowering plasma calcium levels. The worry with a loop diuretic is that in the absence of adequate intravascular volume expansion, the hypercalciuria might be made worse via increasing proximal sodium and consequently calcium reabsorption. The addition of a therapeutic agent that uncouples urinary sodium from calcium excretion, such as an ETA/ETB inhibitor, could theoretically be of significant use. It would permit the excretion of calcium, while enabling the protection of plasma volume by permitting tubular sodium reabsorption. None declared. The Alexander laboratory is funded by a grant from the Women and Children's Health Research Institute (WCHRI, Canada), which is supported by the Stollery Children's Hospital Foundation, a grant from the Canadian Institutes of Health Research (CIHR, MOP 136891) and the National Science and Engineering Research Council of Canada (RGPIN-2015-05842). R.T.A. is the Canada Research Chair in Renal Tubular Epithelial Transport Physiology.

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