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

doi:10.1016/j.ebiom.2020.103092

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 journal › Article › peer-review

Abstract / Description of output

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 language	English
Article number	103092
Journal	EBioMedicine
Volume	62
Early online date	22 Nov 2020
DOIs	https://doi.org/10.1016/j.ebiom.2020.103092
Publication status	Published - 1 Dec 2020

Keywords / Materials (for Non-textual outputs)

microRNA
Acute liver injury
Kidney function
Signalling
Paracetamol

Access to Document

10.1016/j.ebiom.2020.103092

PIIS2352396420304680Final published version, 2.03 MBLicence: CC BY

Prevention of injury to the kidney by circulating hepatic microRNA
Dear, J., Bailey, M. & Dhaun, N.
UK-based charities
3/01/18 → 2/01/20
Project: Research
An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair
Henderson, N.
UK-based charities
1/08/14 → 31/01/20
Project: Research

Neil Henderson
- Neil.Hendersoned.acuk
- Deanery of Clinical Sciences - Personal Chair of Tissue Repair and Regeneration
- Centre for Inflammation Research
Person: Academic: Research Active (Research Assistant)

Cite this

Matthews, O., Morrison, E., Tranter, J., Starkey Lewis, P., Toor, I., Srivastava, A. H., Sargeant, R. J. E., Rollison, H., Matchett, K., Kendall, T. J., Gray, G. A., Goldring, C. E., Park, K., Denby, L., Dhaun, N., Bailey, M. A., Henderson, N. C., Williams, D., & Dear, J. W. (2020). Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells. EBioMedicine, 62, Article 103092. https://doi.org/10.1016/j.ebiom.2020.103092

@article{fc45b2186dbc4d0e93ae1d76fd580320,

title = "Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells",

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.",

keywords = "microRNA, Acute liver injury, Kidney function, Signalling, Paracetamol",

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

year = "2020",

month = dec,

day = "1",

doi = "10.1016/j.ebiom.2020.103092",

language = "English",

volume = "62",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Matthews, O, Morrison, E, Tranter, J, Starkey Lewis, P, Toor, I, Srivastava, AH, Sargeant, RJE, Rollison, H, Matchett, K , Kendall, TJ , Gray, GA, Goldring, CE, Park, K, Denby, L , Dhaun, N , Bailey, MA , Henderson, NC, Williams, D & Dear, JW 2020, 'Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells', EBioMedicine, vol. 62, 103092. https://doi.org/10.1016/j.ebiom.2020.103092

TY - JOUR

T1 - Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells

AU - Matthews, Olivia

AU - Morrison, Emma

AU - Tranter, John

AU - Starkey Lewis, Philip

AU - Toor, Iqbal

AU - Srivastava, Abhishek H

AU - Sargeant, Rebecca J. E.

AU - Rollison, Helen

AU - Matchett, Kylie

AU - Kendall, Timothy J.

AU - Gray, Gillian A

AU - Goldring, Chris E

AU - Park, Kevin

AU - Denby, Laura

AU - Dhaun, Neeraj

AU - Bailey, Matthew A

AU - Henderson, Neil C

AU - Williams, Dominic

AU - Dear, James W

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

KW - microRNA

KW - Acute liver injury

KW - Kidney function

KW - Signalling

KW - Paracetamol

U2 - 10.1016/j.ebiom.2020.103092

DO - 10.1016/j.ebiom.2020.103092

M3 - Article

SN - 2352-3964

VL - 62

JO - EBioMedicine

JF - EBioMedicine

M1 - 103092

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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Projects

Prevention of injury to the kidney by circulating hepatic microRNA

An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair

Profiles

Neil Henderson

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