Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways
| Autor: | Amany A. Azouz, Fatema Hersi, Fares E.M. Ali, Asmaa Mohammed M. Hussein Elkelawy, Hany A. Omar |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Male
MAPK/ERK pathway NF-E2-Related Factor 2 Glutamate-Cysteine Ligase Calcineurin Inhibitors Pharmacology p38 Mitogen-Activated Protein Kinases Tacrolimus General Biochemistry Genetics and Molecular Biology Nephrotoxicity chemistry.chemical_compound Renin–angiotensin system medicine Animals Rats Wistar General Pharmacology Toxicology and Pharmaceutics Extracellular Signal-Regulated MAP Kinases Kidney Superoxide Dismutase business.industry Angiotensin II General Medicine Rats Uric Acid Enzyme Activation Calcineurin surgical procedures operative medicine.anatomical_structure GCLC Gene Expression Regulation Xanthenes chemistry Uric acid Kidney Diseases Angiotensin-Converting Enzyme 2 business |
| Zdroj: | Life Sciences. 288:120154 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2021.120154 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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