Adenosine A2B receptor mediates cyclosporine counteraction of inflammatory and renal consequences of sepsis in rats.

INTRODUCTION

The immunosuppressant drug cyclosporine A (CsA) demonstrates anti-inflammatory properties in numerous pathological conditions. It acts through modulating T-cell receptor signaling, reducing the expression of inflammatory cytokines, and inhibiting mitochondrial permeability, besides modulating vascular response. These features make it a potential drug to prevent or treat septic acute kidney injury (AKI).

OBJECTIVE

In this study, we investigated whether CsA exerts a protective effect against hemodynamic, inflammatory, and renovascular consequences of sepsis and whether these effects are modulated by adenosine receptor signaling.

MATERIAL AND METHODS

Cecal ligation and puncture (CLP) was utilized to induce sepsis 24 h before hemodynamic and renovascular studies were implicated. Renal vasoconstrictions and vasodilatations were induced by cumulative bolus injections of phenylephrine (PE, 0.41-900 ng) and acetylcholine (ACh, 0.01-7.29 nmol), respectively.

RESULTS

The data showed that CsA abrogated CLP-evoked hypotension, tachycardia, and impaired renovascular responsiveness. Similarly, the elevation in kidney biomarkers together with the pro-inflammatory cytokines (Tumor necrosis factor-alpha (TNFα) and Interleukin-6 (IL-6)) were also blunted after CsA administration. Likewise, the elevation in nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) and decrease in A2BRs renal tubular expression in sepsis was reversed in CsA-treated rats. These advantageous effects of CsA disappeared upon concurrent exposure to the selective A2BR antagonist, Alloxazine.

CONCLUSION

These results suggest a key role for functional A2BR in CsA counteracting CLP-induced hemodynamic, inflammatory, and renal dysfunction in rats.