Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity : Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways
Copyright © 2021 Elsevier Inc. All rights reserved..
AIMS: The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury.
MATERIALS AND METHODS: Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations.
KEY FINDINGS: Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1-7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC.
SIGNIFICANCE: These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1-7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:288 |
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| Enthalten in: |
Life sciences - 288(2022) vom: 01. Jan., Seite 120154 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Azouz, Amany A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.01.2022 Date Revised 10.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.lfs.2021.120154 |
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| 100 | 1 | |a Azouz, Amany A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity |b Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 10.01.2022 | ||
| 500 | |a Date Revised 10.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a AIMS: The calcineurin inhibitor tacrolimus is an effective and widely used immunosuppressant after organ transplantation to reduce graft rejection. However, its nephrotoxic effect could compel the patients to treatment discontinuation. The beneficial effects of angiotensin-converting enzyme 2 (ACE2) on the kidney and other organs have been investigated in several studies, but its role in tacrolimus nephrotoxicity still needs to be elucidated. Our study was designed to investigate effects of the ACE2 activator xanthenone on tacrolimus-induced renal injury | ||
| 520 | |a MATERIALS AND METHODS: Male Wistar rats were administered xanthenone (2 mg/kg) concurrently with tacrolimus (1 mg/kg) for 3 weeks, then blood and kidney tissue samples were collected for biochemical and molecular investigations | ||
| 520 | |a KEY FINDINGS: Co-administration of xanthenone significantly improved renal functions in tacrolimus-treated rats, where serum creatinine, urea, and uric acid levels were close to those of the normal control. Besides, xanthenone reduced renal angiotensin (ANG) II content, while elevated ANG (1-7). Relative protein expressions of p-ERK/ERK and p-p38 MAPK/p38 MAPK inflammatory signals were downregulated upon xanthenone administration with tacrolimus. In addition, xanthenone reinforced antioxidant defense against tacrolimus by enhancing protein expression of the transcription factor Nrf2 with subsequently increased mRNA expressions of the antioxidants SOD3 and GCLC | ||
| 520 | |a SIGNIFICANCE: These protective effects of xanthenone could be attributed to ANG II degradation to ANG (1-7) by ACE2 activation resulting in regulated inflammatory and oxidative responses in the kidney. Therefore, administration of xanthenone along with tacrolimus could be a promising therapeutic strategy to reduce the adverse effects and increase the tolerability to tacrolimus immunosuppressive therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ACE2 activation | |
| 650 | 4 | |a ERK/p38 MAPK | |
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| 700 | 1 | |a Omar, Hany A |e verfasserin |4 aut | |
| 700 | 1 | |a Hersi, Fatema |e verfasserin |4 aut | |
| 700 | 1 | |a Ali, Fares E M |e verfasserin |4 aut | |
| 700 | 1 | |a Hussein Elkelawy, Asmaa Mohammed M |e verfasserin |4 aut | |
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