PT  - JOURNAL ARTICLE
AU  - You-Jin Choi
AU  - Dong Zhou
AU  - Anne Barbosa
AU  - Yongdong Niu
AU  - Xiudong Guan
AU  - Meishu Xu
AU  - Songrong Ren
AU  - Thomas Nolin
AU  - Yiuhua Liu
AU  - Wen Xie
TI  - Activation of constitutive androstane receptor ameliorates renal ischemia-reperfusion induced liver and kidney injury
AID  - 10.1124/mol.117.111146
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.111146
4099  - http://molpharm.aspetjournals.org/content/early/2018/01/18/mol.117.111146.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/01/18/mol.117.111146.full
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.