Abstract
BackgroundBilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases. We investigated whether administration of BIL had a protective effect on cyclosporine (CsA)-induced nephropathy (CIN), and examined the effects of BIL on the oxidative stress and apoptosis.MethodsBIL was pretreated intraperitoneally three times for a week (60 mg/kg), and CsA was injected for 4 weeks (15 mg/kg/day, subcutaneous). Proximal tubular epithelial (HK2) cells were pretreated with 0.1mg/ml of BIL for 24 hours, and then treated with 20 μM of CsA for another 24 hours.ResultsCsA induced marked increases in urine kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) concentrations (P < 0.05). BIL reduced urine Kim-1 in CIN (P < 0.05), while urine NGAL exhibited a decreasing tendency. In CsA-treated rat kidneys, the protein expression of NOX4 and p22phox was reduced by BIL (P < 0.05). BIL ameliorated CsA-induced arteriolopathy, tubulointerstitial fibrosis, tubular injury, and the apoptosis examined by TUNEL assay (P < 0.01). In HK2 cells, BIL reduced intracellular reactive oxygen species in CsA-treated cells. CsA increased the protein expression of bax, cleaved caspase-9, caspase-3 and the activity of caspase-3; however, the anti-apoptotic bcl-2 protein was reduced. These changes were recovered by BIL (P < 0.05).ConclusionsThe direct administration of BIL protected against CsA-induced tubular injury via inhibition of oxidative stress and apoptosis.
Highlights
Bilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases
We investigated whether intraperitoneal administration of BIL had a protective effect on CsAinduced nephropathy (CIN)
We examined the molecular mechanism underlying the effects of BIL on the oxidative stress and apoptosis in CIN
Summary
Bilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases. Bilirubin (BIL) has been shown to exert a protective effect for cardiorenal diseases. A high-normal concentration of serum BIL was related to a decreased risk of cardiovascular disease [1,2,3]. BIL showed beneficial effects in diabetic nephropathy, ischemia reperfusion injury, and contrast-induced nephropathy [4,5,6]. BIL is a breakdown product of heme-containing proteins such as hemoglobin in aging red blood cells. Biliverdin is rapidly converted to BIL by biliverdin reductase [7]. Accumulating evidence has suggested that HO-1 and its product BIL
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