Background Contrast-induced acute kidney injury (CIAKI) is the third most common cause of hospital-acquired AKI. Diabetes mellitus (DM) is a major risk factor for CIAKI. Nevertheless, the mechanism of its role in diabetes susceptibility to CIAKI remains unclear. This study aimed to explore the role played by HDAC9 during the susceptibility of diabetic model to CIAKI.
Methods Both in vitro and in vivo model of diabetes were induced by treating human renal tubular epithelial cells (HK-2) with high glucose (HG, 50mM) and by feeding mice with a high-fat diet (HFD) followed by intraperitoneal injection of streptozotocin (STZ), respectively. CIAKI mice models were constructed by contrast-media (iohexol), and iohexol also was treated HK-2 cells. Then, BRD-4354 (an inhibitor of HDAC9) was added into treated cells and mice. Finally, knockdown HDAC9 in HK-2 cultured with HG, and iohexol was added. The pathological changes, oxidative stress and apoptosis levels in mice kidney tissues were assessed. Meanwhile, cellular reactive oxygen species and the activity of HK-2 cells was measured. Western blot was used to determine the expression of HDAC9 and TXNIP/Trx1/P-ASK1/p38MAPK signaling pathways in cells and kidneys.
Results HDAC9 was increased in both diabetic kidney tissues and HGinduced HK-2 cells. In vitro experiment indicated that HK-2 exposed to HG attenuated further damage to apoptosis and oxidative stress by iohexol via knockdown and inhibiting HDAC9. In vivo assay revealed that BRD4354 reduced diabetic mice sensitivity to CI-AKI. Mechanically, HDAC9 could activate TXNIP/Trx1/P-ASK1/p38MAPK signaling pathway involving in the susceptibility of diabetes to CIAKI.
Conclusion HDAC9 promotes the sensitivity of diabetes to CIAKI; and may be involved in oxidative stress and apoptosis through regulation of the TXNIP/Trx1/P-ASK1/p38MAPK pathway.