Dietary addition of magnesium hydride nanoparticles: a breakthrough in combating high-fat diet-induced chronic kidney disease

Lu, Hongtao1,#; Chen, Wanqiu1,#; Ying, Yajing1,#; Gu, Deqian2; Li, Rui1; Li, Xiangtong1; Cheng, Jin3; Sun, Xuejun1,4; Zhang, Yinyin1,*; Liu, Wenrui5,*;Shen, Hui1,1,


1Department of Naval Medicine, Naval Medical University, Shanghai, China

2No. 980 Hospital of Joint Logistics Support Force, Shijiazhuang, Hebei Province, China

3Internal Medicine III (Nephrology and Endocrinology), Naval Medical Center, Naval Medical University, Shanghai, China

4Department of Nephrology, Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

5Center of Hydrogen Science, Shanghai Jiao Tong University, Shanghai, China

Abstract

A substantial body of evidence indicates a positive correlation between dyslipidemia and an elevated risk of chronic kidney disease, with renal interstitial fibrosis frequently serving as a common pathway in the advanced stages of chronic kidney disease progression. Hydrogen has anti-inflammatory and antioxidant properties, and magnesium hydride nanoparticle is a material with high hydrogen storage capacity. Magnesium hydride -fortified feed is capable of releasing hydrogen gas steadily and continuously within the digestive tract. A 12-week high-fat diet significantly elevated the serum urea and creatinine levels in mice. In contrast, dietary addition of magnesium hydride demonstrated a notable protective effect against pathological conditions. Additionally, magnesium hydride -fortified feed was found to reduce renal fibrosis and thereby improve renal function. In support of these findings, an in vitro study utilizing human kidney cortical proximal tubule epithelial cells (HK-2 cells) exposed to palmitic acid under conditions mimicking a high-fat diet confirmed the renoprotective effects of magnesium hydride. Furthermore, the primary target phosphatase and tensin homologue deleted on chromosome 10 and the molecular mechanisms underlying the effects of magnesium hydride, specifically its ability to inhibit the transforming growth factor-beta -Smad family member 2 and 3 (Smad2/3) axis through downregulating the expression of phosphatase and tensin homologue deleted on chromosome 10, were elucidated. Additionally, overexpression of Hes family BHLH transcription factor 1 can negate the beneficial effects of magnesium hydride, suggesting that Hes family BHLH transcription factor 1 may serve as an upstream regulatory target in the context of the effects of magnesium hydride. In conclusion, this study demonstrated that magnesium hydride functions as a safe and effective hydrogen source capable of inhibiting the activation of the transforming growth factor-beta/Smad2/3 and protein kinase B/mechanistic target of rapamycin pathways by increasing the expression of phosphatase and tensin homologue deleted on chromosome 10. This mechanism counteracts the progression of high-fat diet-induced chronic renal damage.

大量证据表明，血脂异常与慢性肾脏病风险升高呈正相关，而肾间质纤维化常作为慢性肾脏病进展至晚期的共同通路。氢气具有抗炎和抗氧化特性，而氢化镁纳米颗粒是一种高储氢能力的材料。强化氢化镁饲料能在消化道内持续稳定地释放氢气。

12周高脂饮食喂养显著升高了小鼠血清尿素和肌酐水平，而添加氢化镁的饮食则表现出显著的病理保护作用。氢化镁强化饲料还能减轻肾纤维化，从而改善肾功能。体外研究进一步证实了这一发现：在模拟高脂饮食条件下，氢化镁对棕榈酸处理的人肾皮质近端小管上皮细胞（HK-2细胞）具有肾脏保护作用。

研究还阐明了氢化镁作用的核心靶点——第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN），以及其分子机制：通过下调PTEN表达，抑制转化生长因子-β/Smad2/3轴激活。此外，过表达Hes家族BHLH转录因子1可抵消氢化镁的有益效应，提示该因子可能是氢化镁作用的上游调控靶点。

结论表明，氢化镁作为一种安全有效的氢源，能通过增加PTEN表达，抑制转化生长因子-β/Smad2/3和蛋白激酶B/雷帕霉素机制靶点通路的激活，从而阻遏高脂饮食诱导的慢性肾损伤进展。