Impact of the ACE2 activator xanthenone on tacrolimus nephrotoxicity: Modulation of uric acid/ERK/p38 MAPK and Nrf2/SOD3/GCLC signaling pathways

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 th...

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Bibliographic Details
Published in:Life sciences (1973) 2022-01, Vol.288, p.120154, Article 120154
Main Authors: Azouz, Amany A., Omar, Hany A., Hersi, Fatema, Ali, Fares E.M., Hussein Elkelawy, Asmaa Mohammed M.
Format: Article
Language:English
Subjects:
ACE2
ACE2 activation
Angiotensin
Angiotensin II
Angiotensin II - genetics
Angiotensin II - metabolism
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Antioxidants
Calcineurin
Calcineurin inhibitors
Calcineurin Inhibitors - toxicity
Creatinine
Enzyme Activation
ERK/p38 MAPK
Extracellular signal-regulated kinase
Extracellular Signal-Regulated MAP Kinases - genetics
Extracellular Signal-Regulated MAP Kinases - metabolism
Gene Expression Regulation - drug effects
Glutamate-Cysteine Ligase - genetics
Glutamate-Cysteine Ligase - metabolism
Graft rejection
Immunosuppressive agents
Inflammation
Kidney Diseases - chemically induced
Kidney Diseases - drug therapy
Kidney Diseases - metabolism
Kidney Diseases - pathology
Kidneys
Male
MAP kinase
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nrf2/SOD3/GCLC
Organs
p38 Mitogen-Activated Protein Kinases - genetics
p38 Mitogen-Activated Protein Kinases - metabolism
Peptidyl-dipeptidase A
Proteins
Rats
Rats, Wistar
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Tacrolimus
Tacrolimus - toxicity
Transplantation
Urea
Uric acid
Uric Acid - metabolism
Xanthenes - pharmacology
Xanthenone
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Summary: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. 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. 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. 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. [Display omitted] •Tacrolimus induces renal injury via activation of uric acid/ERK/p38 MAPK pathway.•Xanthenone retards the elevation of uric acid, urea, and creatinine by tacrolimus.•Xanthenone reduces renal ANG II and elevates ANG (1–7) in tacrolimus-treated rats.•Xanthenone attenuates ERK/p38 MAPK signaling activation in tacrolimus-treated rats.•Xanthenone enhances the antioxidant defense via Nrf2/SOD3/GCLC signaling.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.120154