Abstract
Hyperuricemia and dyslipidemia are involved in Cd nephrotoxicity. The aim of this study was to determine the effect of quercetin, a dietary flavonoid with anti-hyperuricemic and anti-dyslipidemic properties, on the alteration of renal UA transport system and disorder of renal lipid accumulation in 3 and 6 mg/kg Cd-exposed rats for 4 weeks. Cd exposure induced hyperuricemia with renal XOR hyperactivity and UA excretion dysfunction in rats. Simultaneously, abnormal expression levels of renal UA transport-related proteins including RST, OAT1, MRP4 and ABCG2 were observed in Cd-exposed rats with inhibitory activity of renal Na+-K+-ATPase. Furthermore, Cd exposure disturbed lipid metabolism with down-regulation of AMPK and its downstream targets PPARα, OCTN2 and CPT1 expressions, and up-regulation of PGC-1β and SREBP-1 expressions in renal cortex of rats. We had proved that Cd-induced disorder of renal UA transport and production system might have cross-talking with renal AMPK-PPARα/PGC-1β signal pathway impairment, contributing to Cd nephrotoxicity of rats. Quercetin was found to be effective against Cd-induced dysexpression of RST and OAT1 with XOR hyperactivity and impairment of AMPK-PPARα/PGC-1β signal pathway, resulting in renal lipid accumulation reduction of rats.
Highlights
Cadmium (Cd) is considered to be toxic, heavy metal that causes nephrotoxicity in humans [1,2,3]
We investigated its effects on the expression levels of lipid metabolism-related genes including renal AMP-activated protein kinase (AMPK), its downstream targets peroxisome proliferator-activated receptor α (PPARα), organic cation transporter 2 (OCTN2), carnitine palmityl transferase 1 (CPT1), PPARγ coactivators 1β (PGC-1β), and sterol regulatory element-binding protein 1 (SREBP-1) in rats, demonstrating renal lipid metabolism disorder involved in renal uric acid (UA) transport system dysregulation and Xanthine oxidoreductase (XOR) hyperactivity in Cd nephrotoxicity of rats
UA and XOR are confirmed to be related to lipid metabolism [13], we addressed the question whether Cd nephrotoxicity was correlated to renal lipid metabolism disorder
Summary
Cadmium (Cd) is considered to be toxic, heavy metal that causes nephrotoxicity in humans [1,2,3]. Cd exposure induces the conversion of XDH into XO [7] and causes XO activation [8]. The efflux transporters of the ATP binding cassette (ABC) family such as the multidrug resistance protein 4 (MRP4, ABCC4) [10] and breast cancer-resistance protein (BCRP, ABCG2) [11] seem to be major candidates for urate secretory transport. Abnormality of these renal organic ion transporters may contribute to the impaired UA excretion and hyperuricemia [9,10,11,12]
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