Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI

Abstract

Overexpression of the proximal tubular enzyme -inositol oxygenase (MIOX) induces oxidant stress However, the relevance of MIOX to tubular pathobiology remains enigmatic. To investigate the role of MIOX in cisplatin-induced tubular AKI, we generated conditional MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-knockout (MIOX) mice with tubule-specific MIOX overexpression or knockout, respectively. Compared with cisplatin-treated wild-type (WT) mice, cisplatin-treated MIOX-TG mice had even greater increases in urea, creatinine, and KIM-1 levels and more tubular injury and apoptosis, but these effects were attenuated in cisplatin-treated MIOX mice. Similarly, MIOX-TG mice had the highest and MIOX mice had the lowest renal levels of Bax, cleaved caspase-3, and NADPH oxidase-4 expression and reactive oxygen species (ROS) generation after cisplatin treatment. , cisplatin dose-dependently increased ROS generation in LLC-PK1 cells. Furthermore, MIOX overexpression in these cells accentuated cisplatin-induced ROS generation and perturbations in the ratio of GSH to oxidized GSH, whereas MIOX-siRNA or-acetyl cysteine treatment attenuated these effects. Additionally, the cisplatin-induced enhancement of p53 activation, NF-B binding to DNA, and NF-B nuclear translocation in WT mice was exacerbated in MIOX-TG mice but absent in MIOX mice. , MIOX-siRNA or NAC treatment reduced the dose-dependent increase in p53 expression induced by cisplatin. We also observed a remarkable influx of inflammatory cells and upregulation of cytokines in kidneys of cisplatin-treated MIOX-TG mice. Finally, analysis of genomic DNA in WT mice revealed cisplatin-induced hypomethylation of the MIOX promoter. These data suggest that MIOX overexpression exacerbates, whereas MIOX gene disruption protects against, cisplatin-induced AKI.

Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

“…Interestingly, treatment with deferoxamine (an iron chelator) and Z-VAD(OMe)-FMK (an apoptosis inhibitor) also led to increased survival of the cells (Figure 2, J and K). However, treatment with necrostatin-1 (Nec-1; a necroptosis inhibitor) did not restore the viability of cells treated with cisplatin (Fig-dent on demethylation of MIOX promoter in a diabetic state or cisplatin-induced AKI (8,14). Upregulated MIOX expression also promotes the generation of reactive oxygen species (ROS), and thus it conceivably exacerbates renal tubular injury in a variety of pathological states.…”

“…Cisplatin-induced nephropathy has been extensively investigated in various animal models to explore the pathogenesis of AKI. Previous studies have shown that cisplatin is reabsorbed from the glomerular ultrafiltrate in proximal tubules, and it leads to severe ATN due to the DNA damage, cellular redox imbalance, and mitochondrial dysfunctions (7,8). Recently, cisplatin was noted to induce death of cancer cells via different processes, including ferroptosis (9).…”

“…It has been reported that ferroptosis is incriminated in the pathogenesis of many diseases, such as Huntington's disease, Parkinson's disease, hemochromatosis, urinary tract infections, and death of neoplastic cells following chemotherapy (9)(10)(11). Owing to the abundance of polyunsaturated fatty acids in renal tubular cells (8), it is conceivable that the kidney is readily susceptible to lipid hydroperoxide-induced ferroptosis. In fact, it has been shown that the process of ferroptosis is more relevant than necroptosis and apoptosis in IRI-induced ATN, and it is also the primary cause of folic acid-induced AKI (9,12), but its role in cisplatin-induced AKI remains to be explored.…”

“…It catabolizes myo-inositol to d-glucuronate, and plays an important role in renal tubular injury (14). The MIOX promoter includes osmotic response elements, carbohydrate response elements, oxidant response elements, and sterol response elements, and thus MIOX transcription is modulated by oxidant stress, high glucose ambience, and the administration of free fatty acids (8,14,15). Besides, epigenetic studies have revealed that MIOX expression is depen-Overexpression of myo-inositol oxygenase (MIOX), a proximal tubular enzyme, exacerbates cellular redox injury in acute kidney injury (AKI).…”

Concise review: Current and emerging biomarkers of nephrotoxicity

“…In vitro studies show MIOX overexpression leads to enhanced generation of ROS in the presence of cisplatin [38]. Dutta et al observed, using both MIOX null and overexpressing mice, that MIOX null mice are resistant to cisplatin-induced nephrotoxicity whereas MIOX overexpressing mice displayed enhanced injury [39]. In work by Gaut et al investigators developed an immunoassay to detect plasma MIOX as a biomarker of AKI in both animal and human species.…”