Abstract
Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group): (1) vehicle infusion group, (2) aldosterone infusion group, or (3) aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.
Highlights
Aldosterone secreted from the adrenal cortex increases the reabsorption of sodium and water by activating epithelial sodium channels (ENaCs) in the collecting ducts of the kidneys [1]
The present study demonstrated that immunosuppressant therapy with mizoribine alleviates renal inflammation and cell death accompanied by caspase-1 activation in aldosterone-salttreated rats
The data of this study suggest that mizoribine inhibits the accumulation of inflammatory cells and prevents the upregulation of IFN-c, tumor necrosis factor (TNF)-a, and monocyte chemotactic protein (MCP)-1 mRNA induced by the aldosterone infusion
Summary
Aldosterone secreted from the adrenal cortex increases the reabsorption of sodium and water by activating epithelial sodium channels (ENaCs) in the collecting ducts of the kidneys [1]. Heptinstall et al developed a salt-sensitive rat model, which was induced by mineralocorticoid infusion [13]. This model showed pathologic findings of massive interstitial inflammation and fibrosis as well as physiologic features of severe hypertension and urinary protein excretion. Renal inflammation is reported to be associated with the development and progression of renal fibrosis [15]. These findings indicate that aldosterone-induced inflammation could serve as a therapeutic target for resolving saltsensitive hypertension and renal fibrosis
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