Journal
PHARMACEUTICS
Volume 15, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics15051373
Keywords
tacrolimus; nephrotoxicity; mineralocorticoid receptors
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Tac treatment can lead to hypertension, nephrotoxicity, and increased aldosterone levels. The mineralocorticoid receptor (MR) plays a role in the proinflammatory response and vascular contraction in the kidney. This study showed that the MR expressed in vascular smooth muscle cells (SMC) is involved in the renal damage caused by Tac. Administration of an MR antagonist or targeted deletion of MR in SMC mitigated the adverse effects of Tac.
Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects.
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