Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Kidney Int. 2022 Jan;101(1):63-78. doi: 10.1016/j.kint.2021.09.030. Epub 2021 Nov 1.
Autophagy regulator beclin 1 activity determines the severity of kidney damage induced by ischemia reperfusion injury, but its role in kidney recovery and fibrosis are unknown and its therapeutic potentials have not been tested. Here, we explored beclin 1 effects on kidney fibrosis in three models of acute kidney injury (AKI)-ischemia reperfusion injury, cisplatin kidney toxicity, and unilateral ureteric obstruction in mouse strains with three levels of beclin 1 function: normal (wild type), low (heterozygous global deletion of beclin 1, Becn1), and high beclin 1 activity (knockin gain-of-function mutant Becn1, Becn1). Fourteen days after AKI induction, heterozygous mice had more, but knockin mice had less kidney fibrosis than wild-type mice did. One day after ischemia reperfusion injury, heterozygous pan-kidney tubular Becn1 null mice had more severe kidney damage than homozygous distal tubular Becn1 null mice did, which was similar to the wild-type mice, implying that proximal tubular beclin 1 protects the kidney against ischemia reperfusion injury. By 14 days, both pan-kidney heterozygous Becn1 null and distal tubular homozygous Becn1 null mice had poorer kidney recovery than wild-type mice did. Injection of beclin 1 peptides increased cell proliferation in kidney tubules in normal mice. Beclin 1 peptides injection either before or after (2-5 days) ischemia reperfusion injury protected the kidney from injury and suppressed kidney fibrosis. Thus, both endogenous beclin 1 protein expression in kidney tubules and exogenous beclin 1 peptides are kidney protective via attenuation of acute kidney damage, promotion of cell proliferation, and inhibition of kidney fibrosis, consequently improving kidney recovery post-AKI. Hence, exogenous beclin 1 peptide may be a potential new therapy for AKI.
自噬调节因子 beclin 1 的活性决定了缺血再灌注损伤引起的肾脏损伤的严重程度，但它在肾脏恢复和纤维化中的作用尚不清楚，其治疗潜力也尚未得到检验。在这里，我们在三种急性肾损伤 (AKI) 模型中，即缺血再灌注损伤、顺铂肾毒性和单侧输尿管梗阻中，在三种 beclin 1 功能水平的小鼠品系中探索了 beclin 1 对肾脏纤维化的影响：正常（野生型）、低（beclin 1 杂合性全局缺失，Becn1）和高 beclin 1 活性（敲入功能获得性突变体 Becn1，Becn1）。AKI 诱导后 14 天，杂合子小鼠的肾脏纤维化程度更高，但敲入子小鼠的肾脏纤维化程度比野生型小鼠低。缺血再灌注损伤后 1 天，杂合子全肾管状 Becn1 完全缺失小鼠的肾脏损伤比同源性远端管状 Becn1 完全缺失小鼠严重，与野生型小鼠相似，这表明近端肾小管 beclin 1 可保护肾脏免受缺血再灌注损伤。14 天后，全肾杂合子 Becn1 完全缺失和远端肾小管同源性 Becn1 完全缺失小鼠的肾脏恢复均比野生型小鼠差。Beclin 1 肽在正常小鼠的肾脏小管中注射可增加细胞增殖。在缺血再灌注损伤之前或之后（2-5 天）注射 beclin 1 肽可保护肾脏免受损伤并抑制肾脏纤维化。因此，肾脏小管中的内源性 beclin 1 蛋白表达和外源性 beclin 1 肽均通过减轻急性肾损伤、促进细胞增殖和抑制肾脏纤维化来保护肾脏，从而改善 AKI 后的肾脏恢复。因此，外源性 beclin 1 肽可能是 AKI 的一种潜在新疗法。
