Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020

Wall, Susan M.

doi:10.1161/hypertensionaha.121.16492

Cited by 10 publications

(8 citation statements)

References 117 publications

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“…The b-ICs of the cortical collecting duct control acid-base balance and also modulate our body fluid volume. 45 In addition to the SCTR, pendrin (SLC26A4), and CFTR, several other membrane proteins seem to have key roles in mediating/regulating urinary base excretion. The SLC4A9 (AE4) transporter, a suggested Na 1 -coupled HCO 3 2 transporter, was recently identified to play a critical role in regulation of pendrin function and to permit increases in renal base excretion 46 In addition, also the IRR is strongly expressed in the b-ICs and has an important role in regulating urine base excretion.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

Berg

Jensen

Andersen

et al. 2023

JASN

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Background The secretin receptor (SCTR) is functionally expressed in the basolateral membrane of the β-intercalated cells of the kidney cortical collecting duct and stimulates urine alkalization by activating the β-intercalated cells. Interestingly, the plasma secretin level increases during acute metabolic alkalosis, but its role in systemic acid–base homeostasis was unclear. We hypothesized that the SCTR system is essential for renal base excretion during acute metabolic alkalosis. Methods We conducted bladder catheterization experiments, metabolic cage studies, blood gas analysis, barometric respirometry, perfusion of isolated cortical collecting ducts, immunoblotting, and immunohistochemistry in SCTR wild-type and knockout (KO) mice. We also perfused isolated rat small intestines to study secretin release. Results In wild-type mice, secretin acutely increased urine pH and pendrin function in isolated perfused cortical collecting ducts. These effects were absent in KO mice, which also did not sufficiently increase renal base excretion during acute base loading. In line with these findings, KO mice developed prolonged metabolic alkalosis when exposed to acute oral or intraperitoneal base loading. Furthermore, KO mice exhibited transient but marked hypoventilation after acute base loading. In rats, increased blood alkalinity of the perfused upper small intestine increased venous secretin release. Conclusions Our results suggest that loss of SCTR impairs the appropriate increase of renal base excretion during acute base loading and that SCTR is necessary for acute correction of metabolic alkalosis. In addition, our findings suggest that blood alkalinity increases secretin release from the small intestine and that secretin action is critical for bicarbonate homeostasis.

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Section: Discussionmentioning

confidence: 99%

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

Berg

Jensen

Andersen

et al. 2023

JASN

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“…11 Similarly, our findings highlight the predominant role of non–type A ICs in maintaining water and NaCl homeostasis. 11,55–57 The reduction in pendrin expression together with the likely defect in H + -ATPase activity as seen in the DOCA/HCO 3 − model explains the more pronounced alkalosis. Although extremely rare, the association of severe alkalosis with primary dRTA or Pendred syndrome has been reported in infants treated with thiazide diuretics.…”

Section: Discussionmentioning

confidence: 99%

The B1 H+-ATPase (Atp6v1b1) Subunit in Non–Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis

Bourgeois,

Kovacikova,

Bugarski

et al. 2023

JASN

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Background Non–type A ICs in the collecting duct system express the luminal Cl−/HCO3 − exchanger pendrin and apical and/or basolateral H+-ATPases containing the B1 subunit isoform. Non–type A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type A ICs. The function of B1 in non–type A ICs has remained elusive. Methods We examined the responses of Atp6v1b1 −/− and Atp6v1b1 +/+ mice to an alkali load and to chronic treatment with furosemide. Results An alkali load or 1 week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1 −/− versus Atp6v1b1 +/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non–type A ICs of ex vivo microperfused cortical collecting ducts were reduced, and β 2-adrenergic stimulation of pendrin activity was blunted in ATP6v1b1 −/− mice. Basolateral H+-ATPase activity was strongly reduced, although the basolateral expression of the B2 isoform was increased. Ligation assays for H+-ATPase subunits indicated impaired assembly of V0 and V1 H+-ATPase domains. During chronic furosemide treatment, ATP6v1b1 −/− mice also showed polyuria and hyperchloremia versus Atp6v1b1 +/+ . The expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced. Conclusions Our data demonstrate a critical role of H+-ATPases in non–type A ICs function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H+-ATPase complexes assembly and ability to be stimulated.

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“…In addition, a recent study has shown that, in the late distal convoluted tubules, ENaC is likely regulated by glucocorticoids [58]. Therefore, intricate and coordinated actions of MR-dependent and -independent signaling optimize NaCl transport mechanisms in the distal nephron, thereby precisely controlling salt handling in the segment [52,59,60].…”

Section: Electrolyte Handling In Renal Tubulesmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges

Fujii

Shibata

2023

IJMS

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Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of environmental perturbations and how their dysregulation compromises fluid homeostasis. In addition to these roles, the accumulation of data also provided unequivocal evidence that MR is involved in the pathophysiology of kidney diseases. Experimental studies delineated the diverse pathological consequences of MR overactivity and uncovered the multiple mechanisms that result in enhanced MR signaling. In parallel, clinical studies consistently demonstrated that MR blockade reduces albuminuria in patients with chronic kidney disease. Moreover, recent large-scale clinical studies using finerenone have provided evidence that the non-steroidal MR antagonist can retard the kidney disease progression in diabetic patients. In this article, we review experimental data demonstrating the critical importance of MR in mediating renal injury as well as clinical studies providing evidence on the renoprotective effects of MR blockade. We also discuss areas of future investigation, which include the benefit of non-steroidal MR antagonists in non-diabetic kidney disease patients, the identification of surrogate markers for MR signaling in the kidney, and the search for key downstream mediators whereby MR blockade confers renoprotection. Insights into these questions would help maximize the benefit of MR blockade in subjects with kidney diseases.

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Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020

Cited by 10 publications

References 117 publications

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

The B1 H+-ATPase (Atp6v1b1) Subunit in Non–Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis

Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges

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