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

Autor:	Matthews O; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Morrison EE; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Tranter JD; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Starkey Lewis P; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, United Kingdom., Toor IS; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Srivastava A; AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom., Sargeant R; AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom., Rollison H; AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom., Matchett KP; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Kendall TJ; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Gray GA; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Goldring C; Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom., Park K; Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom., Denby L; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Dhaun N; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Bailey MA; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom., Henderson NC; 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., Williams D; AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom., Dear JW; Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom. Electronic address: james.dear@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2020 Dec; Vol. 62, pp. 103092. Date of Electronic Publication: 2020 Nov 21.
DOI:	10.1016/j.ebiom.2020.103092
Abstrakt:	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. Competing Interests: Declaration of Competing Interest Author JWD is a member of the expert advisory group for the EU IMI funded TransBioLine Consortium. Author LD supervises a PhD studentship co-funded by Regulus Therapeutics and GSK. (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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