Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells

Abstract

Background Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney. Methods Dicer flox/flox mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO). Organ microRNA expression was measured in health and following paracetamol toxicity. The functional consequence of hepatic microRNA transfer was determined by measuring the expression and activity of cytochrome P450 2E1 (target of the hepatocellular miR-122), and by measuring the effect of serum extracellular vesicles (ECVs) on proximal tubular cell injury. In humans with liver injury we measured microRNA expression in urinary ECVs. A murine model of myocardial infarction was used as a non-hepatic model of microRNA release. Findings Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury –miR-499 was released following cardiac injury and correlated with an increase in the kidney. Interpretation Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function. Funding Kidney Research UK, Medical Research Scotland, Medical Research Council.

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

“…Circulating miRs may perform signaling functions in peripheral tissues. For example, miR-122-5p influenced the development of obesity, diabetes, and cardio-metabolic syndrome and regulated kidney xenobiotic metabolism ( Matthews et al. 2020 ; Singhal et al.…”

Possible Role of Extracellular Vesicles in Hepatotoxicity of Acetaminophen

“…Refs. [ 91 , 92 , 93 ], are mainly localized in hepatocytes, and they play a key role in the oxidation and metabolism of xenobiotics and endogenous compounds, and thus, are a primary defense against toxic reagents [ 91 , 92 , 93 , 94 , 95 , 96 ]. Additionally, this superfamily of enzymes has other important endogenous functions.…”

Systems analysis of miRNA biomarkers to inform drug safety

“…The nature and significance of miR half-life requires more research, such as by Matthews et al (2020). Here, under inhibition of further hepatocyte miR production miR-122 was shown to have a shorter half-life than ALT despite a large endogenous release (Matthews et al 2020).…”

“…Half-life of miR-122 in blood is estimated to be less than both ALT and AST, returning to baseline after 3-7 days, which may be indicative of progression and resolution of liver injury (Starkey Lewis et al 2011). The nature and significance of miR half-life requires more research, such as by Matthews et al (2020). Here, under inhibition of further hepatocyte miR production miR-122 was shown to have a shorter half-life than ALT despite a large endogenous release (Matthews et al 2020).…”