Abstract
Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Osteopontin (OPN) has been implicated in the pathology of several renal conditions. This study was to evaluate the effects of OPN on hypercholesterolemia induced renal dysfunction. Eight-week-old male mice were divided into 4 groups: apolipoprotein E knockout (ApoE−/−) and ApoE/OPN knockout (ApoE−/−/OPN−/−) mice fed a normal diet (ND) or high cholesterol diet (HD). After 4 weeks, Periodic acid-Schiff (PAS) and oil red O staining revealed excessive lipid deposition in the glomeruli of ApoE−/−HD mice, however, significantly suppressed in ApoE−/−/OPN−/−HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression was lower in the glomeruli of ApoE−/−/OPN−/−HD mice than ApoE−/−HD mice. In vitro study, primary mesangial cells were incubated with recombinant mouse OPN (rmOPN). RmOPN induced LOX-1 mRNA and protein expression in primary mesangial cells. Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia.
Highlights
Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD)
total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) were lower in ApoE−/−/ OPN−/− mice than in ApoE−/− mice with both normal diet (ND) and high cholesterol diet (HD) treatment
Triglycerides (TG) in ApoE−/− mice and ApoE−/−/OPN−/− mice treated with HD were lower than in ApoE−/− mice and ApoE−/−/OPN−/− mice treated with ND, respectively
Summary
Hypercholesterolemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Pre-treatment with an ERK inhibitor suppressed the LOX-1 gene expression induced by rmOPN. These results indicate that OPN contributes to kidney damage in hypercholesterolemia and suggest that inhibition of OPN may provide a potential therapeutic target for the prevention of hypercholesterolemia. In apoE−/− mice, dyslipidemia-related kidney injury is associated with marked pathological alterations, including lipid deposition in the glomerulus, mesangial expansion, and increased extracellular matrix (ECM) area[2,3]. LOX-1 binds to multiple ligands, has diverse physiological functions, and plays a critical role in signal transduction. It may be a key factor in the development of hypertension, diabetes mellitus, and hyperlipidemia[6,7,8]. The function of OPN in hypercholesterolemia-induced renal injury is not clear
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