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Lovastatin attenuates hypertension induced by renal tubule-specific knockout of ATP-binding cassette transporter A1, by inhibiting epithelial sodium channels
- Source :
- Br J Pharmacol
- Publication Year :
- 2018
-
Abstract
- Background and purpose We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP-binding cassette transporter A1; ABCA1). Experimental approach We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell-attached patch-clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail-cuff method. Key results Specific deletion of ABCA1 elevated BP and ENaC single-channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. Conclusions and implications These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol-dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4-2, increased furin expression, and reduced cilium-mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA-induced hypertension.
- Subjects :
- 0301 basic medicine
Epithelial sodium channel
Male
03 medical and health sciences
0302 clinical medicine
Western blot
medicine
Epithelial Sodium Channel Blockers
Animals
Lovastatin
Epithelial Sodium Channels
Furin
Antihypertensive Agents
Pharmacology
Mice, Knockout
biology
medicine.diagnostic_test
Kinase
Chemistry
urogenital system
Cilium
Anticholesteremic Agents
Research Papers
Cell biology
030104 developmental biology
Kidney Tubules
ABCA1
Hypertension
SGK1
biology.protein
lipids (amino acids, peptides, and proteins)
030217 neurology & neurosurgery
medicine.drug
ATP Binding Cassette Transporter 1
Subjects
Details
- ISSN :
- 14765381
- Volume :
- 176
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- British journal of pharmacology
- Accession number :
- edsair.doi.dedup.....17f8e714652067baaf7b07a3302d66a3