Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama, Japan.
PLoS One. 2022 Mar 16;17(3):e0265512. doi: 10.1371/journal.pone.0265512. eCollection 2022.
The heme component of myoglobin plays a crucial role in the pathogenesis of rhabdomyolysis-associated acute kidney injury (RM-AKI). Heme oxiganenase-1 (HO-1) is the rate-limiting enzyme of heme catabolism, and its metabolites, iron, biliverdin, and carbon monoxide, have antioxidant properties. Tin chloride (SnCl2) is a kidney specific HO-1 inducer. In this study, we examined whether the induction of HO-1 in the kidney by SnCl₂ pretreatment ameliorates RM-AKI in rats and if the effect is due to the degradation of excess renal free heme. We developed an RM-AKI rat (male Sprague-Dawley rats) model by injecting glycerol (Gly) in the hind limbs. RM-AKI rats were pretreated with saline or SnCl₂ or additional SnMP (tin mesoporphyrin, a specific HO inhibitor) followed by Gly treatment. Serum blood urea nitrogen (BUN) and creatinine (Crea) were measured as indicators of renal function. Renal free heme level was assessed based on the levels of δ-aminolevulinate synthase (ALAS1), a heme biosynthetic enzyme, and nuclear BTB and CNC homology 1 (Bach1), an inhibitory transcription factor of HO-1. Elevated free heme levels lead to decreases in ALAS1 and nuclear Bach1. After 24 h of Gly injection, serum BUN and Crea levels in saline-pretreated rats were significantly higher than those in untreated control rats. In contrast, SnCl₂-pretreated rats showed no significant increase in the indices. However, additional treatment of SnMP abolished the beneficial effect of SnCl₂. Renal ALAS1 mRNA levels and renal nuclear Bach1 protein levels in the saline pretreated rats were significantly lower than those in control rats 3 h after Gly injection. In contrast, the levels in SnCl₂-pretreated rats were not altered. The findings indicate that SnCl2 pretreatment confers protection against RM-AKI by virtue of HO-1 induction in the renal system, at least in part through excess free heme degradation.
肌红蛋白的血红素组件在横纹肌溶解相关急性肾损伤（RM-AKI）的发病机制中起着关键作用。血红素加氧酶-1（HO-1）是血红素分解代谢的限速酶，其代谢产物铁、胆红素和一氧化碳具有抗氧化特性。氯化锡（SnCl2）是一种肾脏特异性 HO-1 诱导剂。在这项研究中，我们研究了 SnCl2 预处理诱导肾脏 HO-1 是否可以改善大鼠的 RM-AKI，以及这种作用是否是由于降解过多的肾内游离血红素所致。我们通过在下肢注射甘油（Gly）建立了 RM-AKI 大鼠（雄性 Sprague-Dawley 大鼠）模型。RM-AKI 大鼠用盐水或 SnCl2 或额外的 SnMP（锡原卟啉，一种特定的 HO 抑制剂）预处理，然后用 Gly 处理。血清血尿素氮（BUN）和肌酐（Crea）被用作肾功能的指标。根据血红素生物合成酶 δ-氨基酮戊酸合酶（ALAS1）和核 BTB 和 CNC 同源性 1（Bach1），即 HO-1 的抑制性转录因子的水平来评估肾内游离血红素水平。游离血红素水平升高会导致 ALAS1 和核 Bach1 水平降低。在 Gly 注射 24 小时后，用盐水预处理的大鼠的血清 BUN 和 Crea 水平明显高于未处理的对照组大鼠。相比之下，SnCl2 预处理的大鼠的这些指标没有显著增加。然而，额外的 SnMP 处理消除了 SnCl2 的有益作用。在用 Gly 注射后 3 小时，盐水预处理的大鼠的肾 ALAS1 mRNA 水平和肾核 Bach1 蛋白水平明显低于对照组大鼠。相比之下，SnCl2 预处理的大鼠的这些水平没有改变。这些发现表明，SnCl2 预处理通过在肾脏系统中诱导 HO-1 来赋予 RM-AKI 保护作用，至少部分是通过降解过多的游离血红素。
