Abstract
BackgroundExtracellular 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.MethodsDicerflox/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.FindingsDicer-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.InterpretationPhysiological 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.FundingKidney Research UK, Medical Research Scotland, Medical Research Council.
Highlights
MicroRNAs are key regulators of gene expression [1]
Liver depletion of Dicer resulted in a time-dependent decrease in miR-122, miR-192 and miR-151 (Fig. 1 and S4)
The work described in this paper demonstrates that miR-122 is transferred from the liver to the kidney tubular cells as a physiological process that is increased by acute liver injury
Summary
MicroRNAs are key regulators of gene expression [1]. The primary microRNA transcript is cleaved in the cell nucleus to release a pre-y co-first authorsResearch in contextEvidence before the studyThe commonest cause of acute liver injury is paracetamol (acetaminophen) overdose. It is established that a microRNA species, miR-122, is highly expressed in hepatocytes It is released into the circulation in high concentration following paracetamolinduced liver injury in human disease and murine models. The functional consequence of hepatic microRNA transfer was determined by measuring the expression and activity of cytochrome P450 2E1 (target of the hepatocellular miR122), and by measuring the effect of serum extracellular vesicles (ECVs) on proximal tubular cell injury. MiR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Transfer of microRNA was not restricted to liver injury ÀmiR-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.
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