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Salvage of cyclosporine A-induced oxidative stress and renal dysfunction by carvedilol
Satyanarayana S V Padi1, Kanwaljit Chopra
1Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Background:
Cyclosporine A (CsA) is the first-line immunosuppressant employed for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA nephrotoxicity. The present study was designed to investigate effects of carvedilol, a third-generation beta-blocker with potent free radical-scavenging activity on CsA-induced oxidative stress and resultant renal dysfunction in a rat model of chronic CsA nephrotoxicity.
Methods:
Carvedilol (2.0 and 4.0 mg/kg i.p.) and propranolol (10 mg/kg i.p.) were administered to separate group of animals 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Tissue lipid peroxidation was measured as thiobarbituric acid-reacting substances (TBARS). Renal morphological alterations were assessed by histopathological examination of hematoxylin-eosin, PAS and Masson's trichrome stained sections of the kidneys.
Results:
CsA (20 mg/kg s.c) administration for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Propranolol neither decreased TBARS nor improved the renal dysfunction and morphological changes induced by CsA. Both doses of carvedilol markedly reduced elevated levels of TBARS, whereas the higher dose of carvedilol significantly attenuated renal dysfunction and morphological changes in CsA-treated rats.
Conclusions:
These data clearly indicate the renoprotective potential of carvedilol in CsA-induced nephrotoxicity and suggest a significant contribution of its antilipoperoxidative property in this beneficial effect.
Insights
Carvedilol demonstrates renoprotective effects against cyclosporine A (CsA)-induced kidney damage by reducing oxidative stress. This study highlights carvedilol
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cyclosporine A (CsA) is a primary immunosuppressant for organ transplantation and autoimmune diseases.
- Nephrotoxicity is a significant limitation of CsA therapy.
- Reactive oxygen species (ROS) are implicated in CsA-induced kidney damage.
Purpose of the Study:
- To investigate the protective effects of carvedilol against CsA-induced nephrotoxicity.
- To evaluate the role of carvedilol's antioxidant properties in mitigating CsA's renal side effects.
Main Methods:
- Rats were treated with CsA (20 mg/kg) for 21 days.
- Carvedilol (2.0 and 4.0 mg/kg) or propranolol (10 mg/kg) were administered concurrently with CsA.
- Renal function, oxidative stress (TBARS), and kidney histology were assessed.
Main Results:
- CsA treatment led to impaired renal function, increased oxidative stress (TBARS), and severe kidney damage.
- Propranolol did not offer protection against CsA-induced nephrotoxicity.
- Carvedilol significantly reduced TBARS levels and attenuated renal dysfunction and morphological changes, particularly at the higher dose.
Conclusions:
- Carvedilol exhibits significant renoprotective potential in CsA-induced nephrotoxicity.
- The antilipoperoxidative (antioxidant) activity of carvedilol contributes to its beneficial effects on the kidneys.
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