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Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury.
Experimental Biology and Medicine ( IF 3.2 ) Pub Date : 2020-08-02 , DOI: 10.1177/1535370220946271
Chandrashekar Annamalai 1 , Rajesh N Ganesh 2 , Pragasam Viswanathan 1
Affiliation  

Acute kidney injury causes significant morbidity and mortality. This experimental animal study investigated the simultaneous impact of iron and vitamin D on acute kidney injury induced by iohexol, an iodinated, non-ionic monomeric radiocontrast agent in Wistar rats. Out of 36 healthy male Wistar rats, saline was injected into six control rats (group 1) and iohexol into the remaining 30 experimental rats (groups 2 to 6 comprising six rats each). Biochemical, renal histological changes, and gene expression of iron-regulating proteins and 1 α-hydroxylase were analyzed. Urinary neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, urine protein, serum and urine catalytic iron, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and tissue lipid peroxidation were assayed. Rats injected with iohexol showed elevated urinary NGAL (11.94 ± 6.79 ng/mL), serum creatinine (2.92 ± 0.91 mg/dL), and urinary protein levels (11.03 ± 9.68 mg/mg creatinine) together with histological evidence of tubular injury and iron accumulation. Gene expression of iron-regulating proteins and 1 α-hydroxylase was altered. Serum and urine catalytic iron levels were elevated (0.57 ± 0.17; 48.95 ± 29.13 µmol/L) compared to controls (0.49 ± 0.04; 20.7 ± 2.62 µmol/L, P < 0.001). Urine catalytic iron positively correlated with tissue peroxidation (r = 0.469, CI 0.122 to 0.667, P = 0.004) and urinary NGAL (r = 0.788, CI 0.620 to 0.887, P < 0.001). 25-hydroxyvitamin D3 (61.58 ± 9.60 ng/mL) and 1,25-dihydroxyvitamin D3 (50.44 ± 19.76 pg/mL) levels increased simultaneously. In a multivariate linear regression analysis, serum iron, urine catalytic iron, and tissue lipid peroxidation independently and positively predicted urinary NGAL, an acute kidney injury biomarker. This study highlights the nephrotoxic potential of catalytic iron besides demonstrating a concurrent induction of vitamin D endogenously for possible renoprotection in acute kidney injury.

Impact statement

This work provides in-depth insights on catalytic iron-induced cytotoxicity and the resultant triggering of endogenous vitamin D synthesis in experimental acute kidney injury. Our results reveal significantly elevated levels of catalytic iron culminating in oxidant-mediated renal injury and a concomitant increase in 1,25-dihdyroxyvitamin D3 levels. Also, changes in other iron-related proteins including transferrin, ferritin, and hepcidin were observed both in the serum as well as in their mRNA expression. We consider all these findings vital since no connection between catalytic iron and vitamin D has been established so far. Furthermore, we believe that this work provides new and interesting results, with catalytic iron emerging as an important target in ameliorating renal cellular injury, possibly by timely administration of vitamin D. It also needs to be seen if these observations made in rats could be translated to humans by means of robust clinical trials.



中文翻译:

内源性维生素 D 在实验性急性肾损伤中的铁毒性及其改善。

急性肾损伤导致显着的发病率和死亡率。这项实验动物研究调查了铁和维生素 D 对 Wistar 大鼠中碘海醇(碘化非离子单体放射造影剂)诱导的急性肾损伤的同时影响。在 36 只健康雄性 Wistar 大鼠中,将生理盐水注射到 6 只对照大鼠(第 1 组),将碘海醇注射到其余 30 只实验大鼠(第 2 至第 6 组,每只大鼠 6 只)。分析了铁调节蛋白和 1 α-羟化酶的生化、肾脏组织学变化和基因表达。测定了尿中性粒细胞明胶酶相关脂质运载蛋白 (NGAL)、血清肌酐、尿蛋白、血清和尿催化铁、25-羟基维生素 D3、1,25-二羟基维生素 D3 和组织脂质过氧化。注射碘海醇的大鼠显示尿 NGAL 升高 (11.94 ± 6. 79 ng/mL)、血清肌酐 (2.92 ± 0.91 mg/dL) 和尿蛋白水平 (11.03 ± 9.68 mg/mg 肌酐) 以及肾小管损伤和铁积累的组织学证据。铁调节蛋白和 1 α-羟化酶的基因表达发生了改变。与对照 (0.49 ± 0.04; 20.7 ± 2.62 µmol/L,P  < 0.001)。尿液催化铁与组织过氧化(r = 0.469,CI 0.122 至 0.667,P  = 0.004)和尿液 NGAL(r = 0.788,CI 0.620 至 0.887,P  < 0.001)呈正相关。25-羟基维生素 D3 (61.58 ± 9.60 ng/mL) 和 1,25-二羟基维生素 D3 (50.44 ± 19.76 pg/mL) 水平同时增加。在多变量线性回归分析中,血清铁、尿催化铁和组织脂质过氧化独立和阳性预测尿 NGAL,一种急性肾损伤生物标志物。该研究强调了催化铁的肾毒性潜力,此外还证明了内源性维生素 D 的同步诱导可能对急性肾损伤的肾脏保护作用。

影响陈述

这项工作为实验性急性肾损伤中催化铁诱导的细胞毒性和由此引发的内源性维生素 D 合成提供了深入的见解。我们的结果显示催化铁水平显着升高,最终导致氧化剂介导的肾损伤,同时 1,25-二羟维生素 D3 水平升高。此外,在血清及其 mRNA 表达中观察到其他铁相关蛋白(包括转铁蛋白、铁蛋白和铁调素)的变化。我们认为所有这些发现都至关重要,因为迄今为止尚未确定催化铁和维生素 D 之间的联系。此外,我们相信这项工作提供了新的和有趣的结果,催化铁成为改善肾细胞损伤的重要靶点,可能是通过及时给予维生素 D。

更新日期:2020-08-02
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