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"Ellison, H"
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KS-WNK1 augments the effects of dietary potassium intake on renal sodium chloride reabsorption
Clinically, potassium supplementation has been shown to lower blood pressure and reduce the risk of stroke through modulation of potassium excretion and sodium reabsorption. Hypokalemia activates the renal sodium chloride cotransporter (NCC) along the distal convoluted tubule (DCT), at least in part, through with-no-lysine 4 (WNK4) kinase and STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) signaling. The DCT also expresses a kinase-deficient, kidney-specific form of WNK1 (KS-WNK1), but its role in NCC activation is unclear. In this issue of the JCI , Boyd-Shiwarski and colleagues found that KS-WNK1 enhanced the effects of potassium on NCC activation in vivo. Specifically, they showed that mice lacking KS-WNK1 did not respond as robustly to dietary challenge. Additionally, in vivo expression of a mutated KS-WNK1 disrupted WNK body, or biomolecular condensate, formation and renal function. These findings, along with those of previous studies, indicate that KS-WNK1 may regulate potassium homeostasis by increasing the kidney’s sensitivity to salt-dependent stress.
Journal Article
Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule
Epidemiological and clinical observations have shown that potassium ingestion is inversely correlated with arterial hypertension prevalence and cardiovascular mortality. The higher the dietary potassium, the lower the blood pressure and mortality. This phenomenon is explained, at least in part, by the interaction between salt reabsorption in the distal convoluted tubule (DCT) and potassium secretion in the connecting tubule/collecting duct of the mammalian nephron: In order to achieve adequate K
+
secretion levels under certain conditions, salt reabsorption in the DCT must be reduced. Because salt handling by the kidney constitutes the basis for the long‐term regulation of blood pressure, losing salt prevents hypertension. Here, we discuss how the study of inherited diseases in which salt reabsorption in the DCT is affected has revealed the molecular players, including membrane transporters and channels, kinases, and ubiquitin ligases that form the potassium sensing mechanism of the DCT and the processes through which the consequent adjustments in salt reabsorption are achieved.
Graphical Abstract
In this review, G. Gamba
et al
present the current knowledge on the regulation of sodium and potassium homeostasis in the distal convoluted tubule, and the related control of blood pressure.
Journal Article
Insights into Salt Handling and Blood Pressure
Salt intake is associated with blood pressure, but the relationship is complex. This review highlights the interplay among renal salt transport, salt storage in the skin and interstitium, vascular adaptation to changes in the salt concentration, and neurohormonal signaling.
Journal Article
Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake
Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K
+
secretion channel (ROMK) and stimulates urinary K
+
secretion, we explored if Klotho protein is regulated by dietary K
+
and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K
+
secretion have the highest Klotho protein expression along the nephron. WT mice fed K
+
-rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K
+
intake in the K
+
-secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K
+
secretion in humans and mice, ii) In mice, K
+
-rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K
+
intake.
Journal Article
The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension
Calcineurin inhibitors, such as tacrolimus, are widely used immunosuppressive agents, but they can cause hypertension. In studies of tacrolimus-treated mice, the authors show that hypertension is due to activation of the sodium chloride transporter NCC in the kidney, causing sodium retention. They found that NCC activation also occurred in kidney transplant recipients receiving tacrolimus. The authors suggest that thiazide diuretics, which are NCC inhibitors, might counteract the hypertensive effects of this class of immunosuppressants.
Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use
1
,
2
. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.
Journal Article