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Modulation of experimental cyclosporine nephrotoxicity by inhibition of thromboxane synthesis
R Petric1, D Freeman, C Wallace
1Department of Medicine, University Hospital, London, Ontario, Canada.
Abstract:
The clinical usefulness of Cyclosporine is limited by its intrinsic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitor U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2 excretion compared with controls (48.2 +/- 3.1 vs. 24.2 +/- 2.6 ng/24 hr, P less than 0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P less than 0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and CsA-treated rats resulted in a significant reduction in prostanoid excretion. Indomethacin alone had no adverse effect on glomerular function; however, when coadministered with CsA an exaggerated decrease in renal function was observed. CCr in this group fell by a further 27% compared with the CsA-50 group, while FeNa decreased by 76% (P less than 0.001). Histologic injury intensified, with an increase in vacuolization and necrosis. In contrast, coadministration of U63,557A with CsA prevented the rise in urinary TXB2 excretion, improved CCr by 20% (P less than 0.05), and restored FeNa to control levels. The severity of CsA-induced vacuolization was significantly diminished. Selective inhibition of thromboxane production may therefore be valuable in mitigating the clinical nephrotoxicity of CsA.
Insights
Cyclosporine (CsA) causes kidney damage by altering the prostaglandin-thromboxane cascade. Inhibiting thromboxane production with U63,557A protected against CsA-induced nephrotoxicity in rats.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Cyclosporine (CsA) is a vital immunosuppressant, but its clinical use is limited by significant nephrotoxicity.
- A potential mechanism for CsA-induced renal injury involves dysregulation of the prostaglandin-thromboxane (PG-TX) cascade.
Purpose of the Study:
- To investigate the role of the PG-TX system in CsA nephrotoxicity.
- To evaluate the potential renoprotective effects of modulating the PG-TX system using specific inhibitors.
Main Methods:
- Administered CsA (50 mg/kg/day) to Sprague Dawley rats for 7 days.
- Utilized a thromboxane synthetase inhibitor (U63,557A) and a cyclooxygenase inhibitor (indomethacin) to manipulate the PG-TX system.
- Assessed renal function via creatinine clearance (CCr) and fractional excretion of sodium (FeNa), alongside urinary thromboxane B2 (TXB2) levels and histological examination.
Main Results:
- CsA administration significantly increased urinary TXB2 excretion and decreased CCr and FeNa, accompanied by histological renal injury.
- Indomethacin exacerbated CsA-induced nephrotoxicity, worsening renal function and histological damage.
- U63,557A administration prevented the rise in urinary TXB2, improved CCr and FeNa, and reduced histological injury in CsA-treated rats.
Conclusions:
- Selective inhibition of thromboxane production mitigates CsA-induced nephrotoxicity.
- Targeting the PG-TX cascade, specifically thromboxane synthesis, offers a promising therapeutic strategy to reduce the renal side effects of Cyclosporine.