The Anti-inflammatory and Renoprotective Effect of Candesartan May Be Independent of the AT1 Receptor

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.

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• 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.