The molecular mechanism of CFTR‐ and secretin‐dependent renal bicarbonate excretion

Berg, Peder; Svendsen, Samuel L.; Sørensen, Mads Vaarby; Schreiber, Rainer; Kunzelmann, Karl; Leipziger, Jens

doi:10.1113/jp281285

Cited by 19 publications

(13 citation statements)

References 57 publications

(143 reference statements)

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“…Substance P is the hormonal inhibitor of pancreatic bicarbonate secretion that (directly or indirectly) inhibits protein kinase C in pancreatic duct (Hegyi et al, 2005 ). However, Substance P released from renal sensory nerves by prostaglandin E2 (Kopp et al, 2002 ) also acts on the Type B‐IC of the cortical collecting duct via adenylyl cyclase to activate bicarbonate secretion dependent upon both CFTR and Pendrin (Berg et al, 2021 ). A connection between Substance P and protein kinase C stimulation of Pendrin activity has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

Heneghan

Majmundar

Rivera

et al. 2022

Physiological Reports

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SLC26A4/Pendrin is the major electroneutral Cl−/HCO3− exchanger of the apical membrane of the Type B intercalated cell (IC) of the connecting segment (CNT) and cortical collecting duct (CCD). Pendrin mediates both base secretion in response to systemic base load and Cl− reabsorption in response to systemic volume depletion, manifested as decreased nephron salt and water delivery to the distal nephron. Pendrin‐mediated Cl−/HCO3− exchange in the apical membrane is upregulated through stimulation of the β‐IC apical membrane G protein‐coupled receptor, 2‐oxoglutarate receptor 1 (OXGR1/GPR99), by its ligand α‐ketoglutarate (αKG). αKG is both filtered by the glomerulus and lumenally secreted by proximal tubule apical membrane organic anion transporters (OATs). OXGR1‐mediated regulation of Pendrin by αKG has been documented in transgenic mice and in isolated perfused CCD. However, aspects of the OXGR1 signaling pathway have remained little investigated since its original discovery in lymphocytes. Moreover, no ex vivo cellular system has been reported in which to study the OXGR1 signaling pathway of Type B‐IC, a cell type refractory to survival in culture in its differentiated state. As Xenopus oocytes express robust heterologous Pendrin activity, we investigated OXGR1 regulation of Pendrin in oocytes. Despite functional expression of OXGR1 in oocytes, co‐expression of Pendrin and OXGR1 failed to exhibit αKG‐sensitive stimulation of Pendrin‐mediated Cl−/anion exchange under a wide range of conditions. We conclude that Xenopus oocytes lack one or more essential molecular components or physical conditions required for OXGR1 to regulate Pendrin activity.

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Section: Discussionmentioning

confidence: 99%

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

Heneghan

Majmundar

Rivera

et al. 2022

Physiological Reports

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“…In renal intercalated type B (IC-B) cells, we demonstrated regulation of Pendrin activity by CFTR. Lack of expression or dysfunctional CFTR in IC-B cells leads to loss of HCO 3 - secretion in the collecting duct which explains metabolic alkalosis observed in people with cystic fibrosis [ 46 , 47 ]. Although the detailed molecular mechanisms are still missing, the data suggest that CFTR provides luminal Cl- to be recycled by Pendrin, which in turn secretes HCO 3 - ( Figure 2 ).…”

Section: Airway Hco 3 - Secretionmentioning

confidence: 99%

SLC26A9 in airways and intestine: secretion or absorption?

et al. 2023

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SLC26A9 is one out of 11 proteins that belong to the SLC26A family of anion transporters. Apart from expression in the gastrointestinal tract, SLC26A9 is also found in the respiratory system, in male tissues and in the skin. SLC26A9 has gained attention because of its modifier role in the gastrointestinal manifestation of cystic fibrosis (CF). SLC26A9 appears to have an impact on the extent of intestinal obstruction caused by meconium ileus. SLC26A9 supports duodenal bicarbonate secretion, but was assumed to provide a basal Cl- secretory pathway in airways. However, recent results show that basal airway Cl- secretion is due to cystic fibrosis conductance regulator (CFTR), while SLC26A9 may rather secrete HCO 3 -, thereby maintaining proper airway surface liquid (ASL) pH. Moreover, SLC26A9 does not secrete but probably supports reabsorption of fluid particularly in the alveolar space, which explains early death by neonatal distress in Slc26a9-knockout animals. While the novel SLC26A9 inhibitor S9-A13 helped to unmask the role of SLC26A9 in the airways, it also provided evidence for an additional role in acid secretion by gastric parietal cells. Here we discuss recent data on the function of SLC26A9 in airways and gut, and how S9-A13 may be useful in unraveling the physiological role of SLC26A9.

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“…The gastrointestinal hormone secretin stimulates cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin activity. They work in concert promoting bicarbonate secretion in type B intercalated cells in the collecting duct [ 7 ]. Patients with cystic fibrosis carrying a mutation in CFTR show impaired renal excretion of bicarbonate [ 6 ].…”

Section: How Kidneys Support Acid–base Balancementioning

confidence: 99%

“…Patients with cystic fibrosis carrying a mutation in CFTR show impaired renal excretion of bicarbonate [ 6 ]. Authors suggested that secretin would be a bicarbonate-regulating hormone and would be responsible for the elevated bicarbonate excretion after a meal, which is known as alkaline tide [ 7 ]. In addition, a role for pendrin in salt regulation has been proposed, and acid–base changes could also be secondary to changes in extracellular volume [ 122 , 124 ].…”

Section: How Kidneys Support Acid–base Balancementioning

confidence: 99%

Kidney metabolism and acid–base control: back to the basics

Silva

Mohebbi²

2022

Pflugers Arch - Eur J Physiol

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Kidneys are central in the regulation of multiple physiological functions, such as removal of metabolic wastes and toxins, maintenance of electrolyte and fluid balance, and control of pH homeostasis. In addition, kidneys participate in systemic gluconeogenesis and in the production or activation of hormones. Acid–base conditions influence all these functions concomitantly. Healthy kidneys properly coordinate a series of physiological responses in the face of acute and chronic acid–base disorders. However, injured kidneys have a reduced capacity to adapt to such challenges. Chronic kidney disease patients are an example of individuals typically exposed to chronic and progressive metabolic acidosis. Their organisms undergo a series of alterations that brake large detrimental changes in the homeostasis of several parameters, but these alterations may also operate as further drivers of kidney damage. Acid–base disorders lead not only to changes in mechanisms involved in acid–base balance maintenance, but they also affect multiple other mechanisms tightly wired to it. In this review article, we explore the basic renal activities involved in the maintenance of acid–base balance and show how they are interconnected to cell energy metabolism and other important intracellular activities. These intertwined relationships have been investigated for more than a century, but a modern conceptual organization of these events is lacking. We propose that pH homeostasis indissociably interacts with central pathways that drive progression of chronic kidney disease, such as inflammation and metabolism, independent of etiology.

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The molecular mechanism of CFTR‐ and secretin‐dependent renal bicarbonate excretion

Cited by 19 publications

References 57 publications

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

SLC26A9 in airways and intestine: secretion or absorption?

Kidney metabolism and acid–base control: back to the basics

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