The Anti-inflammatory and Renoprotective Effect of Candesartan May Be Independent of the AT1 Receptor
Candesartan belongs to the blockers of AT1 receptors (AT1R) for angiotensin II coupled with G protein. The authors of the presented study found that the anti-inflammatory and renoprotective effect of candesartan persists even when the receptor is completely blocked. The aim of the further study was to clarify this mechanism - independent of AT1R.
Regulation of the Renin-Angiotensin System
The key peptide of the renin-angiotensin system (RAS), angiotensin II, through binding to the AT1 receptor, regulates blood pressure, maintains electrolyte homeostasis, stimulates vasoconstriction, and induces reactive oxygen species.
The AT1R blocker candesartan, which inhibits RAS, is used to treat hypertension, chronic heart failure, and diabetic nephropathy. In a previous in vivo study on a model of chronic kidney damage in spontaneously hypertensive rats, an anti-inflammatory and renoprotective effect of candesartan was observed even with a completely blocked AT1R. This indicates the involvement of mechanisms independent of AT1R. In the following ex vivo study, the authors delve into this mechanism in detail.
Study Methodology
The authors stimulated isolated human embryonic kidney epithelial cells (HKC) with tumor necrosis factor alpha (TNF-α) to induce an inflammatory response. The level of inflammation was assessed based on cytokine expression and the detection of reactive oxygen species (ROS), which arise during inflammatory processes. To investigate the role of AT1R in the anti-inflammatory mechanism of candesartan, they used short interfering RNA (siRNA) to significantly suppress AT1R protein expression.
Results
In HKC exposed to TNF-α in the absence of candesartan, levels of transforming growth factor β (TGF-β) and interleukin 6 (IL-6) significantly increased. In cells simultaneously exposed to candesartan, there was a significant reduction in TGF-β and IL-6 expression induced by TNF-α compared to the control group (p < 0.05). Candesartan significantly suppressed TNF-α induced TGF-β and IL-6 expression even in cells with inactivated AT1R. Hence, AT1R blockade did not impact the candesartan-induced decline in TGF-β and IL-6.
ROS detection revealed that TNF-α significantly increased the presence of reactive oxygen species. Pre-treatment of cells with candesartan or the antioxidant N-acetylcysteine (NAC) visibly reduced TNF-α induced ROS production. This suggests that candesartan may have a similar antioxidant effect as NAC. The reduction in ROS formation due to candesartan was significant even in cells after AT1R inactivation.
Conclusion
Candesartan suppresses TNF-α induced production of inflammatory cytokines more through the inhibition of oxidative stress than AT1R blockade. This fact indicates a direct antioxidant effect of candesartan, which may be particularly beneficial for patients with chronic kidney disease, who often experience ROS overproduction.
(lkt)
- Yu Y., Jiang H., Niu Y. et al. Candesartan inhibits inflammation through an angiotensin II type 1 receptor independent way in human embryonic kidney epithelial cells. An Acad Bras Cienc 2019; 91 (2): e20180699, doi: 10.1590/0001-3765201920180699.
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