Background Ischemia-induced AKI resulting in tubular damage can often progress to CKD and is a common cause of nephrology consultation. After renal tubular epithelial damage, molecular and cellular mechanisms are activated to repair and regenerate the damaged epithelium. If these mechanisms are impaired, AKI can progress to CKD. Even in patients whose kidney function returns to normal baseline are more likely to develop CKD. Genome-wide association studies have provided robust evidence that genetic variants in Shroom3, which encodes an actin-associated protein, are associated with CKD and poor outcomes in transplanted kidneys. Here, we sought to further understand the associations of Shroom3 in CKD. Methods Kidney ischemia was induced in wild-type (WT) and Shroom3 heterozygous null mice (Shroom3Gt/+ ) and the mechanisms of cellular recovery and repair were examined. Results A 28-minute bilateral ischemia in Shroom3Gt/+ mice resulted in 100% mortality within 24 hours. After 22-minute ischemic injury, Shroom3Gt/+ mice had a 16% increased mortality, worsened kidney function, and significantly worse histopathology, apoptosis, proliferation, inflammation, and fibrosis after injury. The cortical tubular damage in Shroom3Gt/+ was associated with disrupted epithelial redifferentiation, disrupted Rho-kinase/myosin signaling, and disorganized apical F-actin. Analysis of MDCK cells showed the levels of Shroom3 are directly correlated to apical organization of actin and actomyosin regulators. Conclusion These findings establish that Shroom3 is required for epithelial repair and redifferentiation through the organization of actomyosin regulators, and could explain why genetic variants in Shroom3 are associated with CKD and allograft rejection.

中文翻译：

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Shroom3 是一种与 CKD 相关的基因，可调节 AKI 后的上皮恢复

背景缺血引起的 AKI 导致肾小管损伤，通常可进展为 CKD，是肾病科咨询的常见原因。肾小管上皮损伤后，分子和细胞机制被激活以修复和再生受损的上皮。如果这些机制受损，AKI 可能会进展为 CKD。即使肾功能恢复到正常基线的患者也更有可能患上 CKD。全基因组关联研究提供了强有力的证据，证明 Shroom3（编码肌动蛋白相关蛋白）的遗传变异与 CKD 和移植肾的不良预后相关。在这里，我们试图进一步了解 Shroom3 在 CKD 中的关联。 方法在野生型（WT）和蘑菇3杂合子无效小鼠（蘑菇3Gt/+）并检查了细胞恢复和修复的机制。 结果28分钟双侧缺血蘑菇3Gt/+小鼠在 24 小时内死亡 100%。22分钟缺血性损伤后，蘑菇3Gt/+小鼠的死亡率增加了 16%，肾功能恶化，损伤后组织病理学、细胞凋亡、增殖、炎症和纤维化明显恶化。皮质管状损伤蘑菇3Gt/+与上皮再分化破坏、Rho 激酶/肌球蛋白信号传导破坏以及顶端 F-肌动蛋白紊乱有关。MDCK 细胞的分析表明 Shroom3 的水平与肌动蛋白和肌动球蛋白调节因子的顶端组织直接相关。 结论这些发现证实，Shroom3 是通过肌动球蛋白调节因子的组织进行上皮修复和再分化所必需的，并且可以解释为什么 Shroom3 的遗传变异与 CKD 和同种异体移植排斥相关。