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Directionally Opposite Effects Of Cyclosporine And Sirolimus On Endotoxic Nephrotoxicity In Rats
Author(s) -
Elzokm Shrouk S.,
Fouda Mohamed A.,
Abdel Moneim Rahab A.,
El-Mas Mahmoud M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01773
Subject(s) - nephrotoxicity , sirolimus , calcineurin , lipopolysaccharide , kidney , creatinine , pharmacology , inflammation , medicine , endocrinology , renal function , transplantation
Immunosuppressant therapies have been shown to protect against inflammation, cardiovascular anomalies, and enhanced mortality during endotoxemia. The current study investigated whether end organ damage caused by endotoxemia is distinctly affected by calcineurin‐dependent (cyclosporine) and independent (sirolimus) immunosuppressants in rats. Biochemical, molecular, and histopathological studies were undertaken to determine the influence of simultaneous exposure to either immunosuppressant on renal and cardiac damage induced by endotoxemia. Serum biomarkers of kidney (urea, creatinine), but not heart (CPK), functions were significantly elevated in rats after 6 hr of treatment with lipopolysaccharide (LPS, 3 mg/kg i.p.). Moreover, LPS caused (i) vacuolation and degeneration of renal tubules, and (ii) significant increases in the width of proximal and distal tubules as appeared from morphometric analysis. Whereas these biochemical and histopathological influences of LPS were intensified upon concurrent exposure to cyclosporine (10 mg/kg i.p.), they were virtually eliminated after co‐treatment with sirolimus (1 mg/kg i.p.). Western expression studies demonstrated that increases in renal protein expressions of toll‐like receptor 4, monocyte chemoattractant protein‐1, and NADPH oxidase 2 were all potentiated and inhibited by cyclosporine and sirolimus, respectively. Unlike kidney data, the assessment of serum CPK or heart morphology revealed no evidence of cardiac abnormalities in rats treated with individual or combined LPS/immunosuppressant regimens. Together, the data underscore the capability of sirolimus, but not cyclosporine, to offset inflammatory and kidney damage in endotoxic states.