Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney cyst growth often resulting in end-stage renal disease. There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) has been shown to increase both protein stability and aggregate clearance and induce autophagy in neurodegenerative diseases. TRE treatment in wild type mice compared to vehicle resulted in increased expression in the kidney of Atg12–5 complex and increased Rab9a, autophagy-related proteins that play a role in the formation of autophagosomes. Thus, the aim of the study was to determine the effect of TRE on cyst growth and autophagy-related proteins, in the hypomorphic Pkd1^RC/RC mouse model of ADPKD. Pkd1^RC/RC mice were treated 2% TRE in water from days 50 to 120 of age. TRE did not slow cyst growth or improve kidney function or affect proliferation and apoptosis in Pkd1^RC/RC kidneys. In Pkd1^RC/RC vs. wild type kidneys, expression of the Atg12–5 complex was inhibited by TRE resulting in increased free Atg12 and TRE was unable to rescue the deficiency of the Atg12–5 complex. Rab9a was decreased in Pkd1^RC/RC vs. wild type kidneys and unaffected by TRE. The TRE-induced increase in p62, a marker of autophagic cargo, that was seen in normal kidneys was blocked in Pkd1^RC/RC kidneys. In summary, the autophagy phenotype in Pkd1^RC/RC kidneys was characterized by decreases in crucial autophagy-related proteins (Atg12–5 complex, Atg5, Atg16L1), decreased Rab9a and increased mTORC1 (pS6^S240/244, pmTOR^S2448) proteins. TRE increased Atg12–5 complex, Rab9a and p62 in normal kidneys, but was unable to rescue the deficiency in autophagy proteins or suppress mTORC1 in Pkd1^RC/RC kidneys and did not protect against cyst growth.

常染色体显性多囊肾病 (ADPKD) 是一种常见的遗传性疾病，其特征是肾囊肿生长，通常会导致终末期肾病。人们越来越关注了解受损自噬在 ADPKD 中的作用。海藻糖 (TRE) 已被证明可以增加蛋白质稳定性和聚集体清除率，并在神经退行性疾病中诱导自噬。与载体相比，野生型小鼠的 TRE 治疗导致 Atg12-5 复合物在肾脏中的表达增加，并增加 Rab9a，自噬相关蛋白在自噬体的形成中发挥作用。因此，该研究的目的是在ADPKD 的亚形 Pkd1 ^RC/RC小鼠模型中确定 TRE 对囊肿生长和自噬相关蛋白的影响。Pkd1 ^RC/RC从 50 天到 120 天，用 2% TRE 水溶液处理小鼠。TRE 不会减缓囊肿生长或改善肾功能或影响Pkd1 ^RC/RC肾脏的增殖和凋亡。在Pkd1 ^RC/RC与野生型肾脏中，Atg12-5 复合物的表达被 TRE 抑制，导致游离 Atg12 增加，并且 TRE 无法挽救 Atg12-5 复合物的缺陷。Rab9a 在Pkd1 ^{RC/RC 中}与野生型肾脏相比降低并且不受 TRE 影响。在正常肾脏中观察到的 TRE 诱导的 p62（自噬货物的标志物）增加在Pkd1 ^RC/RC肾脏中被阻断。总之，Pkd1 ^{RC/RC 中}的自噬表型肾脏的特征是关键自噬相关蛋白（Atg12-5 复合体、Atg5、Atg16L1）减少、Rab9a 减少和 mTORC1（pS6 ^S240/244、pmTOR ^S2448）蛋白增加。TRE 增加了正常肾脏中的 Atg12-5 复合物、Rab9a 和 p62，但无法挽救自噬蛋白的缺乏或抑制Pkd1 ^RC/RC肾脏中的mTORC1，并且不能防止囊肿生长。