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Published on: November 10, 2021
Renal dysfunction potentiates foam cell formation by repressing ABCA1
Yiqin Zuo1, Patricia Yancey, Iris Castro
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-2584, USA.
Insights
Chronic kidney disease (CKD) impairs macrophage cholesterol removal, increasing cardiovascular disease (CVD) risk. Losartan, an angiotensin receptor blocker (ARB), can restore cholesterol efflux in CKD patients, potentially reducing CVD.
Area of Science:
- Cardiovascular Research
- Nephrology
- Macrophage Biology
Background:
- Patients with chronic kidney disease (CKD) face a significantly higher risk of atherosclerotic cardiovascular disease (CVD).
- Existing interventions are insufficient to mitigate the elevated CVD incidence and mortality in CKD patients.
- The precise mechanisms driving this heightened CVD risk in CKD remain unclear, potentially involving altered macrophage cholesterol metabolism.
Purpose of the Study:
- To investigate the impact of renal dysfunction on macrophage cholesterol homeostasis.
- To explore the role of cholesterol trafficking in CKD-associated atherogenesis.
- To evaluate the therapeutic potential of angiotensin receptor blockers (ARBs) in restoring macrophage function.
Main Methods:
- Utilized the apoE(-/-) mouse model of atherosclerosis.
- Induced renal impairment through uninephrectomy.
- Assessed macrophage cholesterol content and efflux capacity.
- Measured expression of ATP-binding cassette transporter A1 (ABCA1) and nuclear factor-kappa B (NF-kappaB) activation.
- Administered the ARB losartan to assess its effects.
Main Results:
- Renal impairment significantly increased macrophage cholesterol content.
- Macrophage cholesterol efflux was markedly impaired in the presence of renal dysfunction.
- This impairment correlated with decreased ABCA1 transporter expression and increased NF-kappaB activation.
- Losartan treatment reduced NF-kappaB activity and restored cholesterol efflux.
Conclusions:
- Mild renal dysfunction disrupts macrophage lipid homeostasis by inhibiting cholesterol efflux.
- This disruption is mediated by reduced ABCA1 transporter levels and activated NF-kappaB.
- Angiotensin receptor blockers (ARBs) demonstrate potential in restoring macrophage cholesterol efflux in the context of renal dysfunction.
Objective:
Patients with chronic kidney disease (CKD) have the highest risk for atherosclerotic cardiovascular disease (CVD). Current interventions have been insufficiently effective in lessening excess incidence and mortality from CVD in CKD patients versus other high-risk groups. The mechanisms underlying the heightened risk remain obscure but may relate to differences in CKD-induced atherogenesis, including perturbation of macrophage cholesterol trafficking.
Methods And Results:
We examined the impact of renal dysfunction on macrophage cholesterol homeostasis in the apoE(-/-) mouse model of atherosclerosis. Renal impairment induced by uninephrectomy dramatically increased macrophage cholesterol content, linked to striking impairment of macrophage cholesterol efflux. This blunted efflux was associated with downregulation of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and activation of the nuclear factor-kappa B (NF-kappaB). Treatment with the angiotensin receptor blocker (ARB) losartan decreased NF-kappaB and restored cholesterol efflux.
Conclusions:
Our findings show that mild renal dysfunction perturbs macrophage lipid homeostasis by inhibiting cholesterol efflux, mediated by decreased ABCA1 transporter and activation of NF-kappaB, and that ARB can restore cholesterol efflux.
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