3.2 | Histone acetylation inhibitors inhibited AAI-induced PANopotosis
To determine which isoforms of HDAC were induced in response to AAI treatment, kidney tissue was harvested at 24, 48, and 72 h after AAI administration. The expression of HDACs was determined using real-time qPCR We found that AAI induced a large increase in HDAC1 and HDAC2 expression, whereas expression of HDAC 3, 4, 7, 8, and 11 was downregulated. (Figure 2A). To determine whether the AAI-induced increase in HDAC expression mediated the AAI-induced nephrotoxicity, FK-228 or vehicle was administered with AAI (Figure 2B). FK-228 administration significantly suppressed kidney dysfunction at 72 h after AAI administration. Saline or FK-228 administration alone did not alter kidney function (Figure 2C). Consistent with the improved kidney function with FK-228 administration, histopathological examinations showed less tubular necrosis, cast formation, and preservation of a brush border in the AAI+FK-228 administered group compared with the AAI+ vehicle-treated group (Figure 2D). In addition, FK-228 treatment impaired the activation of caspase-3 phosphorylated MLKL and GSDMD induced by AAI (Figure 2E, 3A). AAI-induced mTECs were then incubated with FK228. The levels of GSDMD-N, pMLKL, and cleaved caspase-3 expression in AAI-induced mTECs were significantly increased, whereas these levels were sharply decreased in AAI-induced mTECs treated with FK-228 (Figure 3B, C).