Oral Administration of Si-Based Agent Attenuates Oxidative Stress and Ischemia-Reperfusion Injury in a Rat Model: A Novel Hydrogen Administration Method

Organ ischemia-reperfusion injury (IRI), which is unavoidable in kidney transplantation, induces the formation of reactive oxygen species and causes organ damage. Although the efficacy of molecular hydrogen (H2) in IRI has been reported, oral intake of H2-rich water and inhalation of H2 gas are still not widely used in clinical settings because of the lack of efficiency and difficulty in handling. We successfully generated large quantities of H2 molecules by crushing silicon (Si) to nano-sized Si particles (nano-Si) which were allowed to react with water. The nano-Si or relatively large-sized Si particles (large-Si) were orally administered to rats with renal IRI. Animals were divided into four groups: sham, IRI, IRI + nano-Si, and IRI + large-Si. The levels of serum creatinine and urine protein were significantly decreased 72 h following IRI in rats that were administered nano-Si. The levels of oxidative stress marker, urinary 8-hydroxydeoxyguanosine were also significantly decreased with the nano-Si treatment. Transcriptome and gene ontology enrichment analyses showed that the oral nano-Si intake downregulated the biological processes related to oxidative stress, such as immune response, cytokine production, and extrinsic apoptotic signaling pathway. Alterations in the regulation of a subset of genes in the altered pathways were validated by quantitative polymerase chain reaction. Furthermore, immunohistochemical analysis demonstrated that the nano-Si treatment alleviated interstitial macrophage infiltration and tubular apoptosis, implicating the anti-inflammatory and anti-apoptotic effects of nano-Si. In conclusion, renal IRI was attenuated by the oral administration of nano-Si, which should be considered as a novel H2 administration method.

Efficacy of a Si-based agent against developing renal failure in a rat remnant kidney model

Chronic renal failure is exacerbated by oxidative stress, and this condition is difficult to treat in advanced stages. Because of the lack of effective treatments, the disease is a global public health concern. We developed a Si-based agent that continuously generates hydrogen for more than 24 h by reacting with water under conditions similar to those in the gastrointestinal tract. Given the efficacy of hydrogen in the treatment of conditions associated with oxidative stress, we examined whether the Si-based agent had beneficial effects on the development of renal failure. The Si-based agent was orally administered to rats that were developing renal failure. Rats underwent 5/6 nephrectomy to establish a remnant kidney model. Specifically, on day -7, rats underwent right 2/3 nephrectomy, followed by light nephrectomy on day 0. Starting on day -3, the rats were administered a control or Si-based agent-containing diet for 8 weeks. Compared with the findings in control rats, the Si-based agent greatly suppressed the increases of both serum creatinine and urinary protein levels. All analyzed parameters of oxidative stress were significantly suppressed in the Si-based agent groups. Histopathological examination illustrated that glomerular hypertrophy was suppressed by the treatment. Quantitative real-time reverse transcription-polymerase chain reaction revealed that sirtuin 1 and heme oxygenase-1 expression was increased in the Si-based agent groups, suggesting improved antioxidant activity and reduced hypoxia. In addition, caspase-3 and interleukin-6 expression was suppressed in the Si-based agent groups, indicating the alleviation of apoptosis and inflammation. In conclusion, oral administration of a Si-based agent resulted in renoprotective effects, presumably by suppressing oxidative stress via hydrogen generation.