Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States.
Am J Physiol Renal Physiol. 2024 Feb 1;326(2):F178-F188. doi: 10.1152/ajprenal.00184.2023. Epub 2023 Nov 23.
Chronic kidney disease is increasing at an alarming rate and correlates with the increase in diabetes, obesity, and hypertension that disproportionately impact socioeconomically disadvantaged communities. Iron plays essential roles in many biological processes including oxygen transport, mitochondrial function, cell proliferation, and regeneration. However, excess iron induces the generation and propagation of reactive oxygen species, which lead to oxidative stress, cellular damage, and ferroptosis. Iron homeostasis is regulated in part by the kidney through iron resorption from the glomerular filtrate and exports into the plasma by ferroportin (FPN). Yet, the impact of iron overload in the kidney has not been addressed. To test more directly whether excess iron accumulation is toxic to kidneys, we generated a kidney proximal tubule-specific knockout of FPN. Despite significant intracellular iron accumulation in FPN mutant tubules, basal kidney function was not measurably different from wild type kidneys. However, upon induction of acute kidney injury (AKI), FPN mutant kidneys exhibited significantly more damage and failed recovery, evidence for ferroptosis, and increased fibrosis. Thus, disruption of iron export in proximal tubules, leading to iron overload, can significantly impair recovery from AKI and can contribute to progressive renal damage indicative of chronic kidney disease. Understanding the mechanisms that regulate iron homeostasis in the kidney may provide new therapeutic strategies for progressive kidney disease and other ferroptosis-associated disorders. Physiological iron homeostasis depends in part on renal resorption and export into the plasma. We show that specific deletion of iron exporters in the proximal tubules sensitizes cells to injury and inhibits recovery. This can promote a chronic kidney disease phenotype. Our paper demonstrates the need for iron balance in the proximal tubules to maintain and promote healthy recovery after acute kidney injury.
慢性肾脏病的发病率正在以惊人的速度上升，并且与糖尿病、肥胖症和高血压的增加有关，这些疾病不成比例地影响社会经济处于不利地位的社区。铁在许多生物过程中发挥着重要作用，包括氧气运输、线粒体功能、细胞增殖和再生。然而，过量的铁会诱导活性氧的产生和传播，导致氧化应激、细胞损伤和铁死亡。铁稳态部分受肾脏调节，通过从肾小球滤过物中吸收铁，并通过铁蛋白 (FPN) 将其输出到血浆中。然而，铁过载对肾脏的影响尚未得到解决。为了更直接地测试过量铁积累是否对肾脏有毒，我们生成了肾脏近端小管特异性 FPN 敲除小鼠。尽管 FPN 突变小管内的细胞内铁积累显著，但基础肾功能与野生型肾脏没有明显差异。然而，在急性肾损伤 (AKI) 诱导时，FPN 突变肾脏表现出明显更多的损伤和无法恢复，这表明发生了铁死亡，并伴有纤维化增加。因此，近端小管中铁输出的中断导致铁过载，可显著损害 AKI 的恢复，并可导致进行性肾损伤，提示慢性肾脏病。了解调节肾脏中铁稳态的机制可能为进行性肾病和其他铁死亡相关疾病提供新的治疗策略。生理铁稳态部分依赖于肾脏的重吸收和向血浆中的输出。我们表明，近端小管中铁输出器的特异性缺失会使细胞对损伤敏感并抑制恢复。这可能会促进慢性肾脏病的发生。我们的论文表明，在近端小管中保持铁平衡对于在急性肾损伤后维持和促进健康恢复是必要的。
