Inhibition of histone methyltransferase G9a effectively protected the kidney against ischemia-reperfusion injury.

This study examined whether BIX01294, a histone methyltransferase G9a inhibitor, effectively preserves the renal function following acute kidney ischemia-reperfusion (AKIR) injury. Adult-male-SD rats (n = 24) were equally categorized into Group 1 (sham-operated control), Group 2 (AKIR + 1.0 cc N/S I.P. injection), and Group 3 (AKIR + BIX01294/5 mg/Kg by I.P. administration at 3 h after the procedure) and the kidneys were harvested at day-3 post-IR procedure. The results showed that by day 3, the levels of creatinine and the blood urea nitrogen (BUN) were significantly higher in group 3 and more significantly higher in group 2 than in group 1 (all P < 0.0001). The protein expression of upstream (TLR-2/TLR-4/MyD88/TRAF6/p-NF-κB) and downstream (IL-1ß/IL-6/TNF-α) inflammatory signaling molecules exhibited a pattern identical to that of creatinine levels among the groups (all P < 0.0001). The protein expression of oxidative stress (NOX-1/NOX-2), MAP kinase family members (ASK1/MKK4/MKK7/JNK/p-38/p-ERK1/2), apoptosis (cleaved-caspase3/cleaved-caspase8/cleaved-PARP/mitochondrial-Bax), fibrosis (Smad3/TGF-ß), and mitochondrial-damaged markers (cyclophilin D/cytosolic-cytochrome-C) displayed a pattern identical to that of creatinine levels among the groups (all P < 0.0001). The kidney injury score, fibrosis, cellular expression of inflammation (CD68+cells), and glomerulus/renal-tubular damaged markers (Snail/KIM-1/WT-1) exhibited an identical pattern, whereas the cellular expression of podocyte component (synaptopodin) displayed an opposite pattern of creatinine levels among the groups (all P < 0.0001). Therefore, the G9a inhibitor effectively protected kidneys against IR injury. AJTR