Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway

Rozansky, David J.; Cornwall, Tonya; Subramanya, Arohan R.; Rogers, Shaunessy; Yang, Yong; David, Larry L.; Zhu, Xiaoman; Yang, Chao; Ellison, David H.

doi:10.1172/jci38323

Cited by 135 publications

(136 citation statements)

References 53 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…phosphorylates WNK4 and this phosphorylation step reduces the inhibition of WNK4 on NCC 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11 [98,100]. Because SGK1 is sensitive to aldosterone, this pathway appears to be involved in the activation of NCC by aldosterone [100].…”

Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

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

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

show abstract

Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

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

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

“…WNK1 and WNK4 are serine/ threonine kinases that interact in a complex cascade with the STE20-related proline-alanine-rich kinase (SPAK) to regulate NCC phosphorylation (e.g., Thr44, Thr53, Thr58, and Ser71 in mouse NCC) and finally, activity. 8,[10][11][12] In addition to the WNK-SPAK pathway, several other proteins were identified to control NCC, including parvalbumin (PV), 13 serum and glucocorticoid-inducible kinase Sgk1, ubiquitin ligase Nedd4-2, [14][15][16] kelch-like 3 (KLHL3), 17,18 cullin 3, 17,18 and protein phosphatase (PP) 4. 19 Remarkably, several of the above listed regulatory proteins are highly abundant in the DCT (e.g., WNK4, KS-WNK1, SPAK, PV, and KLHL3).…”

mentioning

confidence: 99%

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

Picard

Trompf

Yang

et al. 2014

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelchlike 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na + uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1 2/2 ) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1 2/2 mice. Compared with WT mice, I-1 2/2 mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.

show abstract

“…Because expression of KS-WNK1 is modulated by a dietary K intake, interaction between WNK1 and KS-WNK1 may play a role in regulating ROMK channels and renal K secretion (22). The inhibitory effect of WNK4 is also blocked by SGK1, which phosphorylates WNK4 at Ser 1169 and Ser 1196 (2,5), thereby switching WNK4 from inhibition to stimulation of ROMK channels. The role of Ser 1169 and Ser 1196 in regulating ROMK channels was strongly suggested by the previous finding that mutation of either Ser 1169 or Ser 1196 to aspartate abolished the effect of WNK4 on ROMK channels (13).…”

Section: Ptp-1d Interacts With Wnk4 Via Tyr 1143 To Reduce the Inhibimentioning

confidence: 99%

“…hyperkalemia | hypokalemia | PTP-1D | SGK1 | volume depletion W ith-no-lysine kinase 4 (WNK4) is expressed in the connecting tubule (CNT) and cortical collecting duct (CCD) (1,2) and plays an important role in modulating the balance between renal K secretion and Na reabsorption (3)(4)(5)(6)(7)(8). The effect of WNK4 on renal K secretion is partially mediated through inhibition of KCNJ1 (ROMK) channels in the CNT and in the CCD.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Lin

Yue

Yarborough

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis. This effect is inhibited via phosphorylation at Ser1196 by serum/glucocorticoidinduced kinase 1 (SGK1), and this inhibition is attenuated by the Srcfamily protein tyrosine kinase (SFK). Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr 1092 , Tyr 1094 , and Tyr 1143 , and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. Mutation of Tyr 1092 or Tyr 1143 to phenylalanine decreased the association of c-Src or PTP-1D with WNK4, respectively. Moreover, the Tyr1092Phe mutation markedly reduced ROMK inhibition by WNK4; this inhibition was completely absent in the double mutant WNK4 Y1092/1094F . Similarly, c-Src prevented SGK1-induced phosphorylation of WNK4 at Ser 1196 , an effect that was abrogated in the double mutant. WNK4 Y1143F inhibited ROMK activity as potently as wild-type (WT) WNK4, but unlike WT, the inhibitory effect of WNK4 Y1143F could not be reversed by SGK1. The failure to reverse WNK4 Y1143F -induced inhibition of ROMK by SGK1 was possibly due to enhancing endogenous SFK effect on WNK4 by decreasing the WNK4-PTP-1D association because inhibition of SFK enabled SGK1 to reverse WNK4 Y1143F -induced inhibition of ROMK. We conclude that WNK4 is a substrate of SFKs and that the association of c-Src and PTP-1D with WNK4 at Tyr 1092 and Tyr 1143 plays an important role in modulating the inhibitory effect of WNK4 on ROMK.W ith-no-lysine kinase 4 (WNK4) is expressed in the connecting tubule (CNT) and cortical collecting duct (CCD) (1, 2) and plays an important role in modulating the balance between renal K secretion and Na reabsorption (3-8). The effect of WNK4 on renal K secretion is partially mediated through inhibition of KCNJ1 (ROMK) channels in the CNT and in the CCD. ROMK inhibition is achieved by a stimulation of clathrinmediated endocytosis (1), an effect that is dependent on intersectin, a scaffold protein containing two Eps15 homology domains (9).Serum/glucocorticoid-induced kinase 1 (SGK1), a downstream mediator of aldosterone signaling, suppresses the inhibitory effect of WNK4 on ROMK channels through phosphorylation of WNK4 at Ser 1169 (2) and Ser 1196 (5). Both volume depletion and high K intake increase aldosterone and SGK1 levels (10). However, it is not clear why a high K intake or volume depletion modulates differently the effect of SGK1 on ROMK channels.Candidate regulators of differential ROMK expression in hyperkalemia and hypovolemia should be regulated in a potassiumdependent manner. One such protein is the protein tyrosine kinase c-Src, whose expression in renal cortex is reduced in states of high potassium intake (11). We have previously demonstrated a key role of c-Src in determining the effect of SGK1 on WNK4 (12). C-Src abolishes SGK1-induced phosphorylation of WNK4 and restores the inhibit...

show abstract

Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway

Cited by 135 publications

References 53 publications

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

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

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

Contact Info

Product

Resources

About