Abstract
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.
Highlights
The distal nephron is essential for calcium homeostasis
Along the distal convoluted tubule (DCT), the reabsorptive process is transcellular with calcium entering through the apical calcium channel, transient receptor potential cation channel subfamily V member 5 (TRPV5), and exiting via the basolateral plasma membrane calcium ATPase (PMCA) and Na+/ Ca2+ exchanger (NCX) (Boros et al 2009; Dimke et al 2011)
While baseline urinary calcium levels are known to be normal in WNK4À/À animals (Castaneda-Bueno et al 2012; Terker et al 2018), we have reported differences in urine calcium excretion between controls and knockout animals in response to dietary stress (Terker et al 2018)
Summary
The distal nephron is essential for calcium homeostasis. Genetic disruption of distal nephron electroneutral cation-coupled chloride cotransporters, seen in Mendelian salt-wasting tubulopathies, impairs renal calcium handling. Pharmacologic calciuretic phenocopies are observed with loop and thiazide diuretics, which target these nephron segments, further emphasizing the importance of the TAL and DCT in calcium homeostasis. Along the TAL, calcium is reabsorbed primarily via a paracellular pathway (Ferre et al 2012) driven by the lumen positive potential maintained by apical activity of the Na+-K+2Cl- cotransporter (NKCC2) and the renal outer medullary K+ channel (ROMK). Along the DCT, the reabsorptive process is transcellular with calcium entering through the apical calcium channel, transient receptor potential cation channel subfamily V member 5 (TRPV5), and exiting via the basolateral plasma membrane calcium ATPase (PMCA) and Na+/ Ca2+ exchanger (NCX) (Boros et al 2009; Dimke et al 2011)
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