Remote liver injury following acute renal ischaemia–reperfusion: involvement of circulating exosomal miR‐687 and regulation by thymoquinone

Abstract

The pathophysiology of remote hepatic injury following acute renal ischaemiareperfusion injury (IRI) is of particular clinical interest. Secreted small non-coding microRNA (miRs) are thought to exist in exosome-encapsulated form. Thymoquinone (TQ) is the main bioactive ingredient of Nigella sativa and has several renoprotective actions. We expected exosomal miR-687 to be relevant as it could act as a humoral mediator, with possible modulation by TQ. Thirty adult male Wister albino rats were assigned to three groups (n = 10); (1) sham-operated, (2) renal ischaemiareperfusion injury (IRI), and (3) renal IRI pre-treated with TQ 10 mg/kg/day I.V. (TQ-IRI) for 10 days in addition to a dose administered at reperfusion onset. Following 24 h of reperfusion, the IRI group showed renal tissue hypoxia-inducible factor upregulation (P < 0.001). Electron microscopy images of exosomes and analysis of miR-687 revealed elevated levels, which appeared in the circulation. Large amounts of exosomal miR-687 were transmitted to the liver tissue. In the IRI group, liver transaminases (alanine aminotransferase, aspartate aminotransferase) were markedly (P < 0.001) elevated. The hepatic tissue inflammatory markers (vascular cell adhesion molecule-1, myeloperoxidase, monocyte chemotactic protein-1 and nuclear factor-κB) were upregulated (P < 0.001) accompanied with elevated caspase-3. TQ suppressed (P < 0.001) the renal expression and release of exosomal miR-687 into the circulation and its further deposition in the liver tissue; consequently, TQ diminished (P < 0.001) liver tissue inflammation and cellular apoptosis. The results were confirmed by histological tissue assessment. In conclusion, exosomal miR-687 liberated from injured renal tissues into the circulation may be an important factor in inducing remote hepatic injury. Exosomal miR-687 inhibition by TQ protected both renal and hepatic tissues from injury.

From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury

“… 146 , 147 , 148 , 149 , 150 Administration of several cell-derived exosomes facilitates miRNA levels in ischemic kidney tissue or serum. Similarly, most studies on AKI injury have previously been performed using tissues or cells that were experimentally exposed to renal ischemia and reperfusion, 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 as described in Table 3 and Figure 5 and emphasized in the following sections.…”

Nucleic acids and proteins carried by exosomes from various sources: Potential role in liver diseases

“…Fei et al (2021) performed nextgeneration sequencing (NGS) of miRNAs in plasma-derived exosomes and verified that miRNAs-PC-3p-190-42101 in exosomes could reduce the levels of inflammatory factors and protect the liver from HIRI. In a rat model of HIRI, Ashour et al (2021) reported that plasma exosomes had increased levels of miR-687, in addition to increased levels of liver tissue inflammatory markers and caspase-3. Inhibiting the expression of exosomal miR-687 may protect against hepatic injury.…”