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Temporal changes of expression of FXR, Nrf2, α-GST genes in renal failure induced by gentamicin in rat kidney
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Gholamreza Bayat   , Saeed Changizi Ashtiani , Azade Khalili , Roham Mazloom , Mohammadreza Ashrafi |
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Abstract: (252 Views) |
Introduction: Acute kidney injury is a critical clinical issue that could be induced in some susceptible patients following different situations such as cardiac surgeries, consumption of nephrotoxic drugs, and harmful dehydration. There is a growing body of evidence exploring the molecular mechanisms of drug-induced nephrotoxicity. Among them, gentamicin (GM)-induced renal impairment is one of the most practical experimental models to investigate. Farnesoid receptors, one of the nuclear receptor superfamily members, are considered as an upstream controller of cellular redox state. This regulatory role is performed by connecting to several upstream and downstream signaling pathways such as NrF2 which contributes to the formation of glutathione (GSH). The present study was designed to investigate the effects of gentamicin on the time-course pattern of changes in the expression of FXR and some Nrf2-mediated genes involved in cellular antioxidants.
Methods and Materials: Thirty-five male Wistar rats (210±40g) were randomly allocated into five experimental groups including (1) a control group, (2) receiving gentamicin for three consecutive days (GM-3d), (3) receiving gentamicin for seven consecutive days (GM-7d), (4) receiving gentamicin for ten consecutive days (GM-10d) and (5) receiving gentamicin for fourteen consecutive days (GM-14d). Gentamicin groups received daily intraperitoneal injection of gentamicin at 100mg/kg for 3,7,10 and 14 days. Biochemical measurement of BUN and Cr, histological assessment of renal samples and molecular analysis using real-time RT-PCR were used to investigate the pattern of expression changes of FXR, Nrf2 and α-GST genes in different levels. A P-value of less than 0.05 was considered statistically significant.
Result: Administration of GM was associated with renal damage was manifested with a significant increase in serum levels of Cr and BUN and proximal tubular damages. Significant elevations of Cr and BUN were started on 7th day and continued up to the 10th and 14th day. Surprisingly a significant reduction in these values occurred on the 14th, when compared to the 10th day. Compared to the control one, the expression of FXR, and Nrf2 significantly diminished at 3th and 7th days, respectively. Moreover, Nrf2, but not FXR expression, was significantly down-regulated on the 10th day. The same pattern was seen for FXR on 14th day. According to between-group comparisons and compared to the 7th day, the expression of FXR was significantly increased at 10th and 14th days. Compared to 7th day, a similar trend was also seen for Nrf2 at 14th day. The expression of the α-GST was associated with a marked elevation at 3th day followed by a dramatic drop on the 7th day. The second time elevation was seen during 10th and 14th days.
Conclusions: The present findings revealed that the expression of FXR, as upstream controller genes and its downstream pathways mediated by Nrf2, could play a role in gentamicin-induced nephrotoxicity but the pattern of expression was rather biphasic at the acute phase or the sub-acute ones.
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| Keywords: Acute kidney injury, Gentamicin, FXR, Nrf2, α-GST |
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Full-Text [PDF 465 kb]
(39 Downloads)
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Type of Study: Research |
Subject:
General
Received: 2024/01/27 | Accepted: 2023/08/1 | Published: 2023/08/1
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