Evidence for a gastrointestinal–renal kaliuretic signaling axis in humans

Preston, Richard A.; Afshartous, David; Rodco, Rolando; Alonso, Alberto B.; Garg, Dyal C.

doi:10.1038/ki.2015.243

Cited by 44 publications

(62 citation statements)

References 41 publications

(85 reference statements)

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“…22 The existence of such feedforward mechanisms has been shown for potassium and salt. [43][44][45][46] However, Scanni et al 23 had found, in healthy humans, that the rate of elimination and overall quantity of Pi excretion did not depend on the route of application (intravenous versus intraduodenal infusion). Consistently, our data do not provide any evidence for a role of the intestine in promoting phosphaturia.…”

Section: Discussionmentioning

confidence: 99%

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

Thomas

Bettoni

Knöpfel

et al. 2016

JASN

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Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH)2-vitamin D3, and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but not gastric Pi loading in parathyroidectomized rats also led to higher creatinine clearance and lower plasma calcium levels but did not reduce the expression or activity of Pi transporters. This evidence suggests that an intravenous or intestinal Pi bolus causes rapid phosphaturia through mechanisms requiring PTH and downregulation of renal Pi transporters but does not support a role of the intestine in stimulating renal clearance of Pi. ABSTRACTPhosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH) 2 -vitamin D 3 , and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but no...

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Section: Discussionmentioning

confidence: 99%

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

Thomas

Bettoni

Knöpfel

et al. 2016

JASN

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“…Additionally, the mechanisms whereby low-K + diet increases PKC activity are currently unknown. Whether hypokalemia, as-yet-unidentified gut-kidney signaling [30], or both, play causative roles are areas for future investigation. Given the evidence that WNK4 amplifies the action of PKC [31], it may also be possible that WNK4 activation by intracellular Cl − depletion is involved in KLHL3 S433-P induction.…”

Section: Discussionmentioning

confidence: 99%

Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3

Ishizawa

Loffing

et al. 2016

Biochemical and Biophysical Research Communications

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Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K+ secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K+ intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K+-mediated activation of Na-Cl cotransporter (NCC) in the kidney. In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels. These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane. Increased phosphorylation of S433 was explained by increased levels of active, phosphorylated protein kinase C (but not protein kinase A), which directly phosphorylates S433. Moreover, in HEK cells expressing KLHL3 and WNK4, we showed that the activation of protein kinase C by phorbol 12-myristate 13-acetate induces KLHL3S433-P and increases WNK4 levels by abrogating its ubiquitination. These data demonstrate the role of KLHL3 in low-K+-mediated induction of NCC; this physiologic adaptation reduces distal electrogenic Na+ reabsorption, preventing further renal K+ loss but promoting increased blood pressure.

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“…External potassium balance includes reactive mechanisms that are either dependent (negative feedback) or independent (feed‐forward) on changes in plasma potassium . Peripheral potassium receptors with afferent connections to the central nervous system are thought to be located in the gastrointestinal tract and these mediate kaliuresis, independent of changes in plasma potassium . Contrary to previous beliefs, aldosterone and vasopressin are not involved in this process .…”

Section: Introductionmentioning

confidence: 95%