Shi Mingjun, Flores Brianna, Gillings Nancy, Bian Ao, Cho Han Jun, Yan Shirley, Liu Yang, Levine Beth, Moe Orson W, Hu Ming Chang
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
Departments of Pathology.
J Am Soc Nephrol. 2016 Aug;27(8):2331-45. doi: 10.1681/ASN.2015060613. Epub 2015 Dec 23.
AKI confers increased risk of progression to CKD. αKlotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of αKlotho expression level to AKI progression to CKD has not been studied. We altered systemic αKlotho levels by genetic manipulation, phosphate loading, or aging and examined the effect on long-term outcome after AKI in two models: bilateral ischemia-reperfusion injury and unilateral nephrectomy plus contralateral ischemia-reperfusion injury. Despite apparent initial complete recovery of renal function, both types of AKI eventually progressed to CKD, with decreased creatinine clearance, hyperphosphatemia, and renal fibrosis. Compared with wild-type mice, heterozygous αKlotho-hypomorphic mice (αKlotho haploinsufficiency) progressed to CKD much faster, whereas αKlotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated αKlotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant αKlotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, αKlotho deficiency and overexpression are associated with lower and higher autophagic flux in the kidney, respectively. Upregulation of autophagy protected kidney cells in culture from oxidative stress and reduced collagen 1 accumulation. We propose that αKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.
急性肾损伤（AKI）会增加进展为慢性肾脏病（CKD）的风险。α-klotho是一种具有细胞保护作用的蛋白质，其在AKI中的表达会降低，但α-klotho表达水平与AKI进展为CKD之间的关系尚未得到研究。我们通过基因操作、磷酸盐负荷或衰老改变全身α-klotho水平，并在两种模型中研究其对AKI后长期预后的影响：双侧缺血再灌注损伤和单侧肾切除加对侧缺血再灌注损伤。尽管肾功能最初看似完全恢复，但两种类型的AKI最终都进展为CKD，伴有肌酐清除率降低、高磷血症和肾纤维化。与野生型小鼠相比，杂合子α-klotho低表达小鼠（α-klotho单倍体不足）进展为CKD的速度要快得多，而α-klotho过表达小鼠在AKI后肾功能保留得更好。高磷饮食会加剧AKI后的α-klotho缺乏，显著增加肾纤维化，并加速CKD进展。AKI后给予重组α-klotho可加速肾脏恢复并减少肾纤维化。与野生型情况相比，α-klotho缺乏和过表达分别与肾脏中较低和较高的自噬通量相关。自噬上调可保护培养中的肾细胞免受氧化应激，并减少胶原蛋白1的积累。我们提出，α-klotho上调自噬，减轻缺血性损伤，减轻肾纤维化，并延缓AKI进展为CKD。
