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

Olivia Matthews, Emma Morrison, John Tranter, Philip Starkey Lewis, Iqbal Toor, Abhishek H Srivastava, Rebecca J. E. Sargeant, Helen Rollison, Kylie Matchett, Timothy J. Kendall, Gillian A Gray, Chris E Goldring, Kevin Park, Laura Denby, Neeraj Dhaun, Matthew A Bailey, Neil C Henderson, Dominic Williams, James W Dear

Research output: Contribution to journalArticlepeer-review

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
Dicerflox/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.
Original languageEnglish
Article number103092
JournalEBioMedicine
Volume62
Early online date22 Nov 2020
DOIs
Publication statusPublished - 1 Dec 2020

Keywords

  • microRNA
  • Acute liver injury
  • Kidney function
  • Signalling
  • Paracetamol

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