Aldosterone does not require angiotensin II to activate NCC through a WNK4–SPAK–dependent pathway

Abstract

We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4–SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin–angiotensin–aldosterone system.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-012-1104-0) contains supplementary material, which is available to authorized users.

Angiotensin-II promotes Na+ uptake in larval zebrafish, Danio rerio, in acidic and ion-poor water

“…It is interesting to note that stimulation of Na C uptake following exposure to low Cl K water was attenuated in the presence of telmisartan (data not shown), indicating that NCC might also be activated by ANG-II within hours. If such regulation indeed takes place, it is most probably posttranslational (e.g., phosphorylation; van der Lubbe et al (2011)). Clearly, the exact identity of the Na C transporters being regulated by ANG-II warrants further investigation.…”

“…Although recent studies have demonstrated independent effects of aldosterone and the RAS on salt reabsorption in the mammalian kidney (van der Lubbe et al 2011(van der Lubbe et al , 2012, the two endocrine systems are intricately linked and indeed the RAS is sometimes referred to as the reninangiotensin-aldosterone system (RAAS). Although fish possess mineralocorticoid receptors (MR; Sturm et al 2005), they lack the capacity to synthesize significant amounts of aldosterone (Colombo et al 1972).…”

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

“…It is clear that aldosterone can increase both NCC expression 33,34,44 and the natriuretic response to thiazides. 45 However, it has not been shown that these effects are the direct consequence of MR activation in DCT cells. NCC is downregulated in mineralocorticoid escape, 46 suggesting that the effect of chronic aldosterone can be overridden by extrinsic factors.…”

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

“…The acute effect of aldosterone only involves phosphorylation of NCC [56], whereas the chronic effect also increases the total protein abundance of NCC [53], which likely occurs independent from changes to NCC mRNA levels [1,69,119]. The regulation of NCC by aldosterone seems logical, because at least the endportion of the DCT expresses the enzyme 11-beta-hydroxysteroid dehydrogenase II which rapidly inactivates glucocorticoids and hence provides mineralocorticoid-sensitivity to the epithelial cells [6].…”