Berg, Peder and Svendsen, Samuel L. and Sorensen, Mads and Larsen, Casper K. and Andersen, Jesper Frank and Jensen-Fangel, Soren and Jeppesen, Majbritt and Schreiber, Rainer and Cabrita, Ines and Kunzelmann, Karl and Leipziger, Jens (2020) Impaired Renal HCO3- Excretion in Cystic Fibrosis. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 31 (8). pp. 1711-1727. ISSN 1046-6673, 1533-3450
Full text not available from this repository. (Request a copy)Abstract
Background Patients with cystic fibrosis (CF) do not respond with increased urinary HCO3- excretion after stimulation with secretin and often present with metabolic alkalosis. Methods By combining RT-PCR, immunohistochemistry, isolated tubule perfusion, in vitro cell studies, and in vivo studies in different mouse models, we elucidated the mechanism of secretin-induced urinary HCO3- excretion. For CF patients and CF mice, we developed a HCO3- drinking test to assess the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in urinary HCO3- excretion and applied it in the patients before and after treatment with the novel CFTR modulator drug, lumacaftor-ivacaftor. Results beta-Intercalated cells express basolateral secretin receptors and apical CFTR and pendrin. In vivo application of secretin induced a marked urinary alkalization, an effect absent in mice lacking pendrin or CFTR. In perfused cortical collecting ducts, secretin stimulated pendrin-dependent Cl-/HCO3- exchange. In collecting ducts in CFTR knockout mice, baseline pendrin activity was significantly lower and not responsive to secretin. Notably, patients with CF (F508del/F508del) and CF mice showed a greatly attenuated or absent urinary HCO3--excreting ability. In patients, treatment with the CFTR modulator drug lumacaftor-ivacaftor increased the renal ability to excrete HCO3-. Conclusions These results define the mechanism of secretin-induced urinary HCO3- excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an in vivo human CF urine test to validate drug efficacy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSMEMBRANE CONDUCTANCE REGULATOR; VASOACTIVE-INTESTINAL-PEPTIDE; BICARBONATE SECRETION; METABOLIC ALKALOSIS; INTERCALATED CELLS; INTRACELLULAR PH; PENDRIN; EXPRESSION; CFTR; EXCHANGER; cystic fibrosis; ion transport; kidney tubule; renal tubular acidosis |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Mar 2021 10:35 |
| Last Modified: | 17 Mar 2021 10:35 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44111 |
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