Electronegative Low-Density Lipoprotein Induces Renal Apoptosis and Fibrosis: STRA6 Signaling Involved

Previous epidemiology studies have demonstrated that dyslipidemia is an important risk factor for the development and progression of chronic kidney disease (1–5). Furthermore, it has been shown that lowering cholesterol concentration with statins might reduce the rate of renal function decline in several clinical trials (6–8). However, mechanisms of lipid-mediated kidney injury have not been well investigated because oxidized LDL (oxLDL) produced by oxidizing LDL with CuSO4 was used in most of these studies (9–14). On the other hand, we have reported that human plasma LDL can be chromatographically divided into five subfractions (L1–L5) with increasing electronegativity. By using native electronegative LDL, we have demonstrated that the most electronegative subfraction, L5, is the only one capable of inducing endothelial cell apoptosis (15, 16), platelet aggregation (17), C-reactive protein overproduction (18), and impairment of endothelial cell regeneration (19, 20). Other investigators have also reported that electronegative LDL can promote TG accumulation in cardiomyocytes (21) and induce inflammasome activation in human macrophages (22). Plasma L5 levels are elevated in patients with high cardiovascular risks, such as hypercholesterolemia and type 2 diabetes (15, 20). Recently, LDL from patients with stage 2 chronic kidney disease was reported to be more electronegative than LDL from control subjects (23). Therefore, it is worthy of investigating whether L5 can cause kidney damage. Vitamin A (retinol) and its derivatives regulate a wide range of crucial biological functions, such as development, differentiation, metabolism, and immunity. Circulating retinol is bound to retinol-binding protein 4 (RBP4) and connects with transthyretin to produce a retinol-RBP4-transthyretin complex (24, 25). This complex is recognized by one RBP4 receptor, termed “stimulated by retinoic acid 6” (STRA6), which transports retinol into cells from the retinol complex (26, 27). The STRA6-mediated translocation of retinol requires the participation of cellular retinol-binding protein 1 (CRBP1), an intracellular retinol acceptor, as well as retinol-metabolizing enzymes, such as lecithin:retinol acyltransferase (28–30). Retinol in cells is thereafter metabolized into retinoic acid (RA). RA exerts its function by binding to cytosolic nuclear receptors, including RA receptors (RARs) and retinoid X receptor (RXR), which can activate the transcription of numerous target genes (24, 25). RA has also been reported to capably inhibit inflammation, apoptosis, and proliferation (31, 32). Furthermore, RA and RARα agonist have been reported to have beneficial effects in several experimental models of kidney diseases (33–36). Accordingly, it is reasonable to hypothesize that STRA6 and its cascades could be altered and involved in pathogenesis of kidney diseases. Therefore, the main goals of this study were to explore: 1) whether L5 treatment can cause kidney apoptosis and fibrosis in L5-treated mice and renal tubule cells; 2) whether L5 treatment can simultaneously alter STRA6, CRBP1, retinol, RA, RARs, and RXRα and 3) whether the alteration of STRA6-mediated cascades are involved in kidney apoptosis and fibrosis caused by L5.