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Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport
- Source :
- Journal of the American Society of Nephrology. 26:2678-2690
- Publication Year :
- 2015
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2015.
-
Abstract
- Kcnj10 encodes the inwardly rectifying K(+) channel Kir4.1 in the basolateral membrane of the distal convoluted tubule (DCT) and is activated by c-Src. However, the regulation and function of this K(+) channel are incompletely characterized. Here, patch-clamp experiments in Kcnj10-transfected HEK293 cells demonstrated that c-Src-induced stimulation of Kcnj10 requires coexpression of caveolin-1 (cav-1), and immunostaining showed expression of cav-1 in the basolateral membrane of parvalbumin-positive DCT. Patch-clamp experiments detected a 40-pS inwardly rectifying K(+) channel, a heterotetramer of Kir4.1/Kir5.1, in the basolateral membrane of the early DCT (DCT1) in both wild-type (WT) and cav-1-knockout (KO) mice. However, the activity of this basolateral 40-pS K(+) channel was lower in KO mice than in WT mice. Moreover, the K(+) reversal potential (an indication of membrane potential) was less negative in the DCT1 of KO mice than in the DCT1 of WT mice. Western blot analysis demonstrated that cav-1 deficiency decreased the expression of the Na(+)/Cl(-) cotransporter and Ste20-proline-alanine-rich kinase (SPAK) but increased the expression of epithelial Na(+) channel-α. Furthermore, the urinary excretion of Mg(2+) and K(+) was significantly higher in KO mice than in WT mice, and KO mice developed hypomagnesemia, hypocalcemia, and hypokalemia. We conclude that disruption of cav-1 decreases basolateral K(+) channel activity and depolarizes the cell membrane potential in the DCT1 at least in part by suppressing the stimulatory effect of c-Src on Kcnj10. Furthermore, the decrease in Kcnj10 and Na(+)/Cl(-) cotransporter expression induced by cav-1 deficiency may underlie the compromised renal transport of Mg(2+), Ca(2+), and K(+).
- Subjects :
- Male
medicine.medical_specialty
Patch-Clamp Techniques
Caveolin 1
Green Fluorescent Proteins
Hypokalemia
Stimulation
Biology
Kidney
Transfection
Membrane Potentials
Hypomagnesemia
Electrolytes
Mice
Internal medicine
medicine
Animals
Humans
Magnesium
Distal convoluted tubule
Potassium Channels, Inwardly Rectifying
Reversal potential
Epithelial polarity
Mice, Knockout
Membrane potential
Cell Membrane
General Medicine
medicine.disease
Mice, Inbred C57BL
HEK293 Cells
Basic Research
Endocrinology
medicine.anatomical_structure
Microscopy, Fluorescence
Nephrology
Potassium
Calcium
Female
medicine.symptom
Cotransporter
Gitelman Syndrome
Subjects
Details
- ISSN :
- 10466673
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology
- Accession number :
- edsair.doi.dedup.....72eacb9a1cd6f036a710ce7e5307c91c