Abstract: TH-PO195
Renal Solute Handling in ABCA1-Deficient Kidneys
Session Information
- Hypertension and CVD: Basic Research Findings
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Carneiro de Oliveira, Karin, James J. Peters VAMC, Bronx, New York, United States
- Wei, Yuan, James J. Peters VAMC, Bronx, New York, United States
- Rohatgi, Rajeev, James J. Peters VAMC, Bronx, New York, United States
Background
Na sensitive blood pressure (BP) and restricted cholesterol (chol) efflux are risk factors for cardiovascular mortality. Renal tubular ablation of ABCA1, a chol efflux protein, raises systolic BP (SBP) compared to wildtype (WT) mice. Enriched chol diets additionally raise SBP in mice of ABCA1 deficient kidneys while Na restriction quenches SBP difference between mice. In contrast enriched Na diets do not further raise SBP in ABCA1 deficient mice. Chol-fed ABCA1 deficient mice show increased renal NKCC2 and ENaC protein expression vs. WT chol-fed mice. The goal of this investigation is to determine whether renal solute transport is dysregulated in ABCA1 deficient mice fed a standard chol diet and whether these changes contribute to the development of high BP.
Methods
Transgenic mice, which express a doxycycline(dox)-inducible CRE in tubules, were bred with mice expressing floxed ABCA1 to produce tubule-specific deficiency of ABCA1 (FF). Mice (WT and FF) were fed dox in water, and then fed a standardNa (0.39%) and chol (0.0196%) for at least 1 week. The mice were then placed in metabolic cages to collect urine at 2 hr intervals for 6 hrs. Urine osmolality and [Na] were measured. RNAseq analysis was performed on the renal cortex.
Results
The weights of WT (n=10; 26.0±0.7 g) and FF (n=10; 25.7±0.4 g) mice did not differ. Surprisingly, FF mice excreted a larger urine volume at 2 hr (15.6±1.4 μL/g body weight[BW]) and over the entire collection period (33.7±2.2 μL/g BW) compared to WT mice (10.5±0.8 uL/g and 25.8± 2.2 uL/g BW, p<0.05; respectively). Urine osmolality did not differ, but osmole excretion was greater over the collection period in the FF (30.2±2.6 μosm/g BW; p<0.05) compared to WT (22.5±2.2 μosm/g BW). The urinary Na concentration rose over 6 hrs in WT and FF, but at 6hr the urine [Na] was greater in FF (97.4±6.9 mM; p<0.05) than WT (57.6±7.6 mM). Net Na excretion was greater in FF (1.49±0.15 μeq/g BW; p<0.05) than WT (0.92±0.17 μeq/g BW). RNAseq showed increased renal cortical Ren1 mRNA and western blot confirmed the increase of renin protein in FF (n=4) compared to WT (n=4).
Conclusion
Renal tubular ABCA1 deficiency, in mice fed a standard Na and chol diet, enhances urine volume, osmolar and Na excretion with greater renal renin expression. We speculate that loss of ABCA1 functionality mediates higher SBP via greater intra-renal renin which raises systemic BP to excrete more Na.
Funding
- Veterans Affairs Support