The role of ABCA1 on glomerular lipid accumulation and renal injury in focal segmental glomerulosclerosis

Abstract

Glomerular lipid accumulation is one of the pathologic characteristics of focal segmental glomerulosclerosis (FSGS). Recent evidence suggests that ATP-binding cassette transporter A1 (ABCA1) has effects on the cellular lipid homeostasis. This study aimed to evaluate the role of ABCA1 on lipid accumulation in glomeruli and podocyte under FSGS conditions. Using human kidney biopsy samples, the expression of the Abca1 mRNA was analyzed in glomeruli in patients with FSGS. In vitro, mouse podocytes were stimulated with adriamycin (ADR) and TNF-α, and these cells were also co-treated with GW683965, an LXR-α agonist to upregulate ABCA1 expression. In vivo, C57BL/6 and podocyte-specific Abca1 knockout mice were administered intravenously with ADR at 25 mg/kg. GW683965 (1 mg/kg/day) was treated via osmotic pumps (10mg/kg/ in ADR-treated BALB/c mice. The levels of albumin in urine, and the levels of cholesterol, and triglyceride in kidney tissues were measured in animals. Active RhoA staining and Bodipy 493/503 staining for glomerular cholesterol assay were performed. Apoptosis- and mitochondrial injury-related markers were evaluated both in vitro and in vivo. Compared to the control group, the levels of albumin in urine, and the levels of cholesterol and triglyceride in the glomeruli were significantly increased and effacement of foot processes assessed by transmission electron microscopy was observed in ADR-induced FSGS mice. These changes were aggravated in podocyte-specific Abca1 knockout FSGS mice, while they were abrogated by GW683965 via upregulation of glomerular ABCA1 expression. The cholesterol and triglyceride contents in kidneys were higher in FSGS models, and were reduced by GW683965. Mitochondrial morphology and the metabolic enzymes were highly deranged in the kidneys of ADR-treated podocyte-specific Abca1 knockout mice. These mitochondrial abnormalities in the FSGS models were improved by replenishing ABCA1 with GW683965 treatment. In vitro, the intracellular lipid contents were increased and subsequent apoptosis and mitochondrial dysfunction were also increased in podocytes treated with ADR and TNF-α. Cellular lipid accumulation and mitochondrial injury by ADR and TNF-α stimuli were ameliorated through GW683965 treatment as an ABCA1 enhancer.