Original Article Serum miRNA-122 in acute liver injury induced by kidney injury and sepsis in CD-1 mouse models Asada Leelahavanichkul, 1,2 Poorichaya Somparn, 3 Thanaporn Panich, 1 Wiwat Chancharoenthana, 2 Jutamas Wongphom, 4 Trairak Pisitkun, 3 Nattiya Hirankarn 1,5 and Somchai Eiam-Ong 2 1 Immunology Unit, Department of Microbiology, 2 Division of Nephrology, Department of Medicine, 3 Research Affairs, 4 Department of Pathology, and 5 Center of Excellence in Immunology and Immune-Mediated Diseases, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Aim: miRNA-122 (miR-122) is a new, interesting liver injury bio- marker but little is known about its effects when there is an indirect acute liver injury. Methods: We investigated this by using indirect liver injury mice models with bilateral ureter obstruction (BUO), bilateral ne- phrectomy (BiNx) and cecal ligation and puncture (CLP). A direct liver injury model, liver ischemia/reperfusion injury (liver I/R), was performed in parallel. Liver injury (i.e. liver histology, alanine transaminase [ALT]), kidney damage (i.e. serum creatinine) and cytokines (i.e. tumor necrosis factor-α, interleukin [IL]-6, IL-1β, IL-10) were assessed. Results: Six hours after BUO/BiNx/CLP, the ALT and serum cyto- kines were approximately 1.5-fold higher than the baseline whereas miR-122 did not change. After 6 h of BiNx, there were prominent hepatocyte vacuolization but no elevations of miR-122. However, after 24 h of BUO/BiNx/CLP, ALT, hepatocyte vacuolization and miR-122 increased. The cytokines at 6 h might have induced the production of miR-122 at 24 h. The results from the in vitro study with HepG2 cells and each of the cytokines resulted in increased miR-122. On the other hand, when the direct liver injury model was used, there was a fivefold and 22-fold increase in the ALT at 0.5 and 1 h after surgery, respec- tively, and high serum miR-122 which corroborated the results from the liver histopathology. Conclusion: We demonstrated that prior serum cytokine accu- mulation increased serum miR-122 in indirect liver injury induced by BUO/BiNx and less severe sepsis mouse models. Cytokine accumulation may be responsible for miR-122 expression in these models. The clinical importance of liver injury demon- strated by the discordance between serum miR-122 and ALT was an interesting issue. Key words: miR-122, acute kidney injury-induced liver injury, sepsis-induced liver injury INTRODUCTION A CUTE KIDNEY INJURY (AKI) is a rapid loss of kidney function from numerous etiologies. AKI causes sev- eral extrarenal organs’ dysfunction (i.e. brain, lungs, heart, intestines and liver) and is sometimes referred to as the “renal and extrarenal organs cross-talk” 1–4 because many of the mechanisms are elicited when there is an abundance of cytokines and induction of reactive oxygen species. 5–7 Hepatic injury is one of the AKI-induced organ dysfunc- tions that occurs before the breakdown of the intestinal barrier which eventually results in multi-organ dysfunc- tion. 1 The high mortality rate of AKI patients in intensive care unit is, at least in part, due to AKI-induced multiple organ damage. 8 Golab et al. showed that renal ischemia/reperfusion (IR) injury and bilateral nephrec- tomy (BiNx) in rats with active hepatic injury was from an accumulation of cytokines and hence recommended monitoring the liver for injury in AKI patients. 9 It is inter- esting that in the BiNx rat model, histology of the liver was able to detect damage as early as 6 h. 9,10 On the other hand, sepsis-induced acute liver injury (ALI) is reported in approximately 12–20% of sepsis patients. 11,12 Multiple mechanisms such as the endotoxin, poor tissue perfusion, Correspondence: Dr Wiwat Chancharoenthana MD., Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Road, Pathumwan, Bangkok 10330, Thailand. Email: wiwatmd@hotmail.com Conflict of interest: All authors declare no financial conflicts of interest. Received 20 June 2014; revision 13 January 2015; accepted 2 February 2015. © 2015 The Japan Society of Hepatology Hepatology Research 2015 doi: 10.1111/hepr.12501