Changes in the expression of miRNAs at the pericentral and periportal regions of the rat liver in response to hepatocellular injury: Comparison with the changes in the expression of plasma miRNAs

Abstract

SDS software v.2.4. The expression levels were evaluated using the comparative cycle 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Statistical analysisThe data are expressed as the means ± SD. The comparisons of two groups were made using Mann-Whitney's U-test. A value of P < 0.05 was considered statistically significant. Results ALT, AST, and histopathology of the liverAfter the administration of APAP and MP, the plasma ALT and AST levels were significantly elevated (Fig. 1A). The histopathological analysis revealed that APAP caused hepatocellular necrosis at the pericentral regions, whereas MP caused hepatocellular necrosis at the periportal region (Fig. 1B). These two models were used for the subsequent studies. miRNA expression at the pericentral and periportal regions of the liverThe miRNA expression at pericentral and periportal regions of the liver was determined by TaqMan microRNA array analysis. The numbers of the detected miRNAs and the miRNAs whose expression exceeded the cutoff (Ct < 32) are shown in Table 1. No large difference was observed in these numbers between the pericentral and periportal regions within a group or between the treated and control groups. Among the miRNAs with Ct values less than 32 in all of the groups, 125 miRNAs were common to all of the groups; therefore, these 125 miRNAs were used for the subsequent analyses. Fig. 2 shows the heat maps of the expression of the 125 miRNAs in each sample; note that the miRNAs are ordered based on descending expression level in the pericentral region of the control rats. The top three miRNAs that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 exhibited high expression in both the pericentral and periportal regions in all of the samples are miR-709, miR-122, and miR-720. The comparison of the miRNA levels between the control rats and fasted-control rats revealed that 36 miRNAs presented higher levels and eight miRNAs exhibited lower levels at the pericentral region of the fasted-control rats (Tables 1 and 2). At the periportal region, 52 miRNAs and two miRNAs presented higher and lower levels, respectively, in the fasted-control rats compared with the control rats. Among these miRNAs, 17 miRNAs, which are shown in bold, were found in both the pericentral and periportal regions. Thus, the results demonstrate that fasting affects the expression of some miRNAs in the liver. The comparison of the miRNA levels between the pericentral and periportal regions in control rats showed that 27 miRNAs exhibited higher expression levels in the pericentral region and that 22 miRNAs presented higher expression levels in the periportal region compared with t...

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

“…There were 17 elevated miRNAs in common between the APAP/CCL 4 treatments (Fig. B), some of which overlapped with another rat APAP model (Yamaura et al , ). Whenever possible, miRNAs between studies were aligned by mature isoforms, but if that information was lacking, the stem–loop name was used to make comparisons.…”

“…( . (B) Elevated miRNAs observed in this study after a single dose with APAP (black circle), CCL 4 (black dashed circle), or in an APAP study by Yamaura et al (. Four underlined miRNAs were identified by the Smith et al () rat miRNA atlas as being liver specific/enriched.…”

“…Both APAP and CCL 4 treatments resulted in a 1.6–2.6‐fold elevation of miR‐155 and miR‐223 in the liver. However, others have suggested that these two miRNAs may be linked to lymphocyte infiltration into areas of damage, so their origin is unclear (Yamaura et al ., ). None of the remaining miRNAs are known to be specific to the kidney or liver (Smith et al ., ).…”

“…The work described here evaluated miRNA biomarkers of acute kidney and liver damage in Sprague–Dawley rats. Plasma, and not serum, was analyzed to keep findings consistent and comparable to other published studies (Church et al ., ; Yamaura et al , ). Significantly elevated plasma and urine miRNAs in identified in this study were compared to published rat studies and to the recently completed rat and dog miRNA atlases.…”

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

“…The authors concluded that suppression of these two miRNAs likely contributes to APAP hepatotoxicity because they are thought to target antioxidant genes [21]. Interestingly, a similar study found that some miRNA changes in the liver were zone specific [22]. Unfortunately, a major drawback of these two studies was the use of rats, which are generally resistant to APAP toxicity and are known to be a poor model of APAP-induced liver injury [23].…”