Abstract: TH-PO0276
Roles Prostaglandins and Renin in ABCA1-Deficient Model of Hypertension (HTN)
Session Information
- Hypertension and CVD: Mechanisms
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Wei, Yuan, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
- Carneiro de Oliveira, Karin, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
- Rohatgi, Rajeev, James J Peters VA Medical Center, New York, New York, United States
Background
Prostaglandin E2 (PGE2), and its interaction with the renin-angiotensin system (RAS) plays critical roles in glomerular and tubular physiology. In the macula densa, PGE2 effectuates renin release to regulate glomerular hydrodynamics while in the distal tubule PGE2 stimulates renin release and augments cation transport. Renin over-expression in tubules induces HTN in mice; while, intrarenal PGE2 infusion raises blood pressure (BP) via activation of RAS. Mice deficient in renal tubular ABCA1 (ABCA1FF), a cholesterol export protein, induces a higher BP compared to wildtype (WT) mice. Cellular cholesterol content also affects cyclooxygenase (COX) expression and regional PGE2 production, and therefore, we hypothesize that deficiency of ABCA1 leads to HTN via activation of COXs, PGE2 and RAS.
Methods
RNA sequencing of renal cortex was performed to identify differentially expressed genes, and these genes were confirmed by immunoblotting. Metabolic cage studies were performed to determine differences in electrolyte transport. Studies were conducted on murine collecting duct cells (mpkccd) in the absence and presence of an ABCA1 inhibitor to study ion transport.
Results
RNAseq analysis of renal cortex revealed robust REN1 mRNA in ABCA1FF compared to WT mice. Immunoblotting of cortex showed increases in renin, and phospho-ERK (pERK). 24 hour urine collection did not identify differences in volume, osmolality, or cation excretion. Urinary renin did not differ, but PGE2 concentration tended to be greater in ABCA1FF than WT. To study mechanism, mpkccd cells were used in conjunction with an ABCA1 antagonist (5 μM, PSC833) to evaluate affected signaling pathways. PSC833 induces pERK, COX2 and renin expression in mpkccd protein lysate, and leads to more basolateral (BL) PGE2 secretion. However, ABCA1 antagonism or PGE2 exposure did not induce immunodetectable renin into the media. Ussing studies showed that BL PGE2 induces an increase in short circuit current (Isc) to raise amiloride sensitive current (Ia) and this effect was more pronounced in PSC833 exposed cells. The PGE2-induced Ia was greater in PSC833 treated (19.3±1.5 μA/cm2) than untreated cells (16.4±1.9 μA/cm2; paired t-test, p<0.05).
Conclusion
Thus, ABCA1 ablation or antagonism induces pERK, COX2, renin and PGE2 secretion to enhance Ia in the renal collecting duct which we speculate contributes to the BP phenotype.
Funding
- Veterans Affairs Support