Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells
Olivia Matthews,
Emma E. Morrison,
John D. Tranter,
Philip Starkey Lewis,
Iqbal S. Toor,
Abhishek Srivastava,
Rebecca Sargeant,
Helen Rollison,
Kylie P. Matchett,
Timothy J. Kendall,
Gillian A. Gray,
Chris Goldring,
Kevin Park,
Laura Denby,
Neeraj Dhaun,
Matthew A. Bailey,
Neil C. Henderson,
Dominic Williams,
James W. Dear
Affiliations
Olivia Matthews
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Emma E. Morrison
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
John D. Tranter
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Philip Starkey Lewis
Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, United Kingdom
Iqbal S. Toor
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Abhishek Srivastava
AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
Rebecca Sargeant
AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
Helen Rollison
AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
Kylie P. Matchett
Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Timothy J. Kendall
Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Gillian A. Gray
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Chris Goldring
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
Kevin Park
Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
Laura Denby
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Neeraj Dhaun
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Matthew A. Bailey
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
Neil C. Henderson
Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, United Kingdom
Dominic Williams
AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
James W. Dear
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom; Corresponding author.
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. Funding: Kidney Research UK, Medical Research Scotland, Medical Research Council.