RT Journal Article
SR Electronic
T1 Activation of constitutive androstane receptor ameliorates renal ischemia-reperfusion induced liver and kidney injury
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.111146
DO 10.1124/mol.117.111146
A1 You-Jin Choi
A1 Dong Zhou
A1 Anne Barbosa
A1 Yongdong Niu
A1 Xiudong Guan
A1 Meishu Xu
A1 Songrong Ren
A1 Thomas Nolin
A1 Yiuhua Liu
A1 Wen Xie
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/01/18/mol.117.111146.abstract
AB Acute kidney injury (AKI) is associate with high mortality. Despite the evidence of AKI-induced distant organ injury, a relationship between AKI and liver injury has not been clearly established. The goal of this study is to investigate whether renal ischemia-reperfusion (IR) can affect liver pathophysiology. We showed that renal IR in mice induced fatty liver and compromised liver function through the down-regulation of constitutive androstane receptor (CAR; -90.4%) and inhibition of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) secretion (-28.4%). Treatment of mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) prevented the development of AKI-induced fatty liver and liver injury, which was associated with the attenuation of AKI-induced inhibition of VLDL-TG secretion. The hepato-protective effect of TCPOBOP was abolished in CAR-/- mice. Interestingly, alleviation of fatty liver by TCPOBOP also improved the kidney function, whereas CAR ablation sensitized mice to AKI-induced kidney injury and lethality. The serum concentrations of IL-6 were elevated by 27-fold after renal IR, but were normalized in TCPOBOP-treated AKI mice, suggesting that the increased release of IL-6 from the kidney may have mediated the AKI responsive liver injury. Taken together, our results have revealed an interesting kidney-liver organ crosstalk in response to AKI. Given the importance of CAR in the pathogenesis of renal IR-induced fatty liver and impaired kidney function, fatty liver can be considered as an important risk factor for kidney injury and a timely management of hepatic steatosis by CAR activation may help to restore kidney function in patients with AKI or kidney transplant.