Myo-inositol oxygenase overexpression exacerbates cadmium-induced kidney injury via oxidant stress and necroptosis

Conceivably, like other forms of acute kidney injury, cadmium-induced renal injury may also be associated with oxidative stress and various forms of cell death, including necroptosis, a form of regulated necrosis-associated cell death. Myo-inositol oxygenase (MIOX), an enzyme localized in renal proximal tubules, regulates oxidative stress and programmed cell death in various forms of renal injuries. Herein, the role and potential mechanism(s) by which MIOX potentiates cadmium-induced renal tubular damage were investigated. Overexpression of MIOX exacerbated cadmium-induced cell death and proximal tubular injury in mice, whereas MIOX gene disruption attenuated cellular damage in vitro and in vivo. Furthermore, necroptosis was observed in the renal tubular compartment, and, more importantly, it was corroborated by inhibitor experiments with necrostatin-1 (Nec-1). Coadministration of Nec-1 dampened including receptor-interacting protein kinase (RIP)1/RIP3/mixed-lineage kinase domain-like signaling, which is relevant to the process of necroptosis. Interestingly, the necroptosis induced by cadmium in tubules was modulated by MIOX expression profile. Also, the increased reactive oxygen species generation and NADPH consumption were accelerated by MIOX overexpression, and they were mitigated by Nec-1 administration. These findings suggest that MIOX-potentiated redox injury and necroptosis are intricately involved in the pathogenesis of cadmium-induced nephropathy, and this may yield novel potential therapeutic targets for amelioration of cadmium-induced kidney injury.NEW & NOTEWORTHY This is a seminal article documenting the role of myo-inositol oxygenase (MIOX), a renal proximal tubule-specific enzyme, in the exacerbation of cadmium-induced acute kidney injury by perturbing redox balance and inducing necroptosis. MIOX gene disruption or administration of necrostatin-1 (a necroptosis inhibitor) diminished cadmium-induced renal damage, in both in vitro and in vivo systems, suggesting a therapeutic potential of MIOX to attenuate necroptosis and relevant signaling pathways in cadmium-induced renal injury.