Role of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in Chemoradiotherapy-induced Renal Injury.

PURPOSE/OBJECTIVE(S): Radiation therapy (RT) alone or combined with chemotherapy reduces cholesterol efflux and causes chronic kidney disease (CKD). There is no treatment for CKD except renal replacement strategies such as dialysis or transplantation. We hypothesize that cancer treatment-induced ABCA1 deficiency leads to dysregulation of cholesterol metabolism, making podocytes susceptible and cancerous cells resistant to treatment-induced injuries.

MATERIALS/METHODS: To quantify the cell index of LNCaP, 786-0, and Podcytes were grown in an e-plate reader (Roche) for 24 h and then were treated with either enzalutamide (10µM) or sunitinib (1.0 µM) or cyclophosphamide (10µM) with or without RT (4Gy) or ABCA1 inducer (liver-X-receptors agonist (GW3965; Sigma; 10µM). Podocyte cholesterol efflux assay was measured using NBD-cholesterol efflux assay, and expression of ABCA1 and cleaved caspase-3 were measured by western blotting. 10-14-week-old C57BL/6 male and female mice were given bilateral kidney X-irradiation of 4Gy with or without cisplatin (3mg/kg; IV). Functional kidney parameters, histopathological changes, and ultrastructural changes were measured at baseline and 20 weeks after treatment. GFR was measured using a FITC-sinistrin-based transdermal monitor.

RESULTS: In vitro studies suggest that after radiation exposure (4Gy and 8Gy), ABCA1 expression decreases in a dose and time-dependent manner in cultured podocytes (p < 0.05), which coincides with reduced cholesterol efflux (p < 0.05) and increased podocyte apoptosis (p < 0.01). In contrast, LXR agonist treatment in vitro prevents reduced ABCA1 expression and cholesterol efflux and prevents podocytes from radiation-induced apoptosis. Our in vitro studies further suggest that Enzalutamide treatment alone reduces the growth of LNCaP and podocytes, and RT (5Gy) plus enzalutamide combination treatment further decreases the growth of LNCaP and podocytes. However, LXR agonist treatment further increased the efficacy of enzalutamide and RT treatment against LNCaP and increased podocyte growth simultaneously. Similarly, Sunitinib with or without RT reduces the growth of renal cancer cells (786-0) and podocytes. LXR agonist treatment further increases the efficacy of the sunitinib and RT against 786-0 cells and simultaneously increases podocyte growth. Cyclophosphamide reduces the growth of the podocytes, and LXR agonist treatment improves the podocyte growth after CP treatment. In vivo studies observed that focal bilateral kidney irradiation with or without cisplatin of C57BL/6 mice induces lipid accumulation in the kidney cortex and increases GBM thickness (p < 0.001), which correlates with decreased Abca1 expression, podocyte number, and GFR.

CONCLUSION: This study shows that LXR agonist treatment protects podocytopathy in vitro and chemotherapy or radiotherapy-induced kidney injury in vivo. ABCA1 may be an important therapeutic target for chemoradiotherapy-induced kidney injuries in cancer patients.