WNK4 limits distal calcium losses following acute furosemide treatment.

Mohammed Z Ferdaus, Brittany D K Gratreak, Lauren Miller, Jinge Si, James A McCormick, Chao-Ling Yang, David H Ellison, Andrew S Terker

Physiological reports 2019 Sep

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The distal nephron is essential for calcium homeostasis. This is evidenced by disordered calcium transport following disrupted distal nephron function occurring in salt-wasting tubulopathies or with diuretic use. A plethora of studies support a role for WNK4 in thick ascending limb (TAL) and distal convoluted tubule ion transport with most studies focusing on sodium transport. Little is known about the in vivo role of WNK4 in regulating calcium homeostsis. Here, we investigated the role of WNK4 in regulating distal nephron calcium transport using WNK4 knockout animals (WNK4-/- ). As has been shown previously, we found that baseline urinary calcium levels are normal following WNK4 deletion. Following acute treatment with the loop diuretic, furosemide, which causes hypercalciuria through TAL inhibition, WNK4-/- animals demonstrated increased calcium wasting compared with wild-type controls. WNK4-/- animals had decreased TRPV5 expression along DCT2 supporting a mechanistic role for this calcium channel in the increased calciuresis. As this supported the hypothesis that WNK4-/- animals have a tendency toward calcium wasting under stress, we tested the effects of a calcium-deplete diet on urinary calcium excretion. Urinary calcium excretion and plasma ionized calcium levels were not different between control and knockout animals following consumption of a calcium-deplete diet. Our data show that WNK4, via regulation of TRPV5, limits distal calcium losses following acute treatment with furosemide; however, WNK4 deletion does not affect the chronic renal response to dietary calcium depletion. Our data reveal an in vivo role for WNK4 in distal nephron calcium handling that is important for fine-tuning calcium reabsorption. © 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Citation

Mohammed Z Ferdaus, Brittany D K Gratreak, Lauren Miller, Jinge Si, James A McCormick, Chao-Ling Yang, David H Ellison, Andrew S Terker. WNK4 limits distal calcium losses following acute furosemide treatment. Physiological reports. 2019 Sep;7(17):e14195