Young Investigator Awardees
Professor James Dear
Acute liver failure (ALF) has no effective treatment other than liver transplantation, which has limited use because of its associated morbidity/mortality, expense and the scarcity of donor livers. In the Western world, paracetamol (acetaminophen) overdose (POD) is the commonest cause of ALF (around 100,000 POD/year in UK). There are at least 1000 POD-ALF cases treated in liver transplant centres in the US and EU (mostly UK) each year. Mortality in this group is around 30-35%, with about 30% receiving a liver transplant. The only treatment for POD is acetylcysteine (NAC), which is only fully effective if started soon after overdose (within 8h). There is no treatment for non-POD ALF. When the liver is injured, renal function is crucial in determining patient outcome. We proposed that the microRNA species, miR-122, released from the injured liver regulates renal function.
Kidney cells internalise microRNA with a subsequent change in gene expression. Circulating microRNAs increase substantially when released from an injured organ, such as following drug-induced liver injury (DILI). We explored whether functional liver-derived microRNA is transferred to the kidney. When liver microRNA was depleted in a mouse model there was a fall in miR-122 (hepatocyte-enriched) in the kidney. Conversely, following DILI there was increased liver-derived miR-122 in kidney tubular cells. Liver-derived microRNA regulated kidney cytochrome P450 2E1 and inhibited toxic injury. This signalling pathway is potentially active in humans – urinary miR-122 was increased with DILI. These findings demonstrate that functional liver microRNA is transferred into kidney tubular cells to regulate gene expression, a signalling mechanism increased by drug toxicity. This microRNA already represents a drug target – miravirsen, a locked nucleic acid-modified DNA antisense oligonucleotide which specifically binds miR-122 – has demonstrated efficacy in a clinical trial to treat hepatitis C. Medicines which target miR-122 may also be effective treatments to prevent renal failure in patients with liver disease.