Mizoribine ameliorates renal injury and hypertension along with the attenuation of renal caspase-1 expression in aldosterone-salt-treated rats.
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.
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Toshiki
T
Doi
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Shigehiro
S
Doi
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Ayumu
A
Nakashima
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Toshinori
T
Ueno
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Yukio
Y
Yokoyama
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Nobuoki
N
Kohno
Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
Takao
T
Masaki
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism*; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000494:pharmacology*; D012492:Salts / Q000494:pharmacology*; D012965:Sodium Chloride / Q000276:immunology / Q000378:metabolism
D053503:Epithelial Sodium Channels; D012263:Ribonucleosides; D012492:Salts; D012965:Sodium Chloride; D000450:Aldosterone; C010052:mizoribine; D004253:DNA Nucleotidylexotransferase; D020170:Caspase 1