Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1^RC/RC and Pkd2^WS25/+ mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1^RC/RC mouse model of PKD. In 70 day old Pkd1^RC/RC hearts, on immunoblot analysis, there was a large increase in p-AMPK^Thr172, a known autophagy inducer, and an increase in p-Akt^Ser473 and p-Akt^Thr308, but no increase in other mTORC1/2 proteins (p-S6^Ser240/244, p-mTOR^Ser2448). In 150 day old Pkd1^RC/RC hearts, there was an increase in mTORC1 (p-S6^Ser240/244) and mTOR-related proteins (p-Akt^Thr308, p-GSK3β^Ser9, p-AMPK^Thr172). As the mTOR pathway is the master regulator of autophagy, autophagy proteins were measured. There was an increase in p-Beclin-1 (BECN1), an autophagy regulator and activating molecule in Beclin-1-regulated autophagy (AMBRA1), a regulator of Beclin that play a role in autophagosome formation, an early stage of autophagy. There was a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70 day old and 150 day old hearts. To determine the role of autophagy in causing increased heart weight, Pkd1^RC/RC were treated with 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide, agents known to induce autophagy. 2-DG treatment from 150 to 350 days of age, a time period when increased heart weight developed, did not reduce the increased heart weight. Unexpectedly, Tat-Beclin 1 peptide treatment from 70 to 120 days of age resulted in increased heart weight. In summary, there is suppressed autophagic flux in the heart at an early age in Pkd1^RC/RC mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPK^Thr172, a known autophagy inducer, in both young and old mice. 2-DG treatment did not impact increased heart weight and Tat-Beclin1 peptide increased heart weight.

心脏肥大在常染色体显性多囊肾病 (ADPKD) 患者中很常见。我们发现ADPKD 的 Pkd1 ^RC/RC和Pkd2 ^WS25/+小鼠模型的心脏重量增加。由于心脏重量增加与哺乳动物雷帕霉素靶标 (mTOR) 之间存在联系，因此本研究的目的是确定PKD的Pkd1 ^RC/RC小鼠模型中心脏中的 mTOR 复合物 1 和 2 信号蛋白。在 70 天大的Pkd1 ^RC/RC心脏中，在免疫印迹分析中，p-AMPK ^Thr172（一种已知的自噬诱导剂）显着增加，p-Akt ^Ser473和 p-Akt ^{Thr308 显着增加}，但其他 mTORC1/2 蛋白（p-S6 ^Ser240/244、p-mTOR ^Ser2448）没有增加。在 150 天龄的Pkd1 ^RC/RC心脏中，mTORC1（p-S6 ^Ser240/244）和 mTOR 相关蛋白（p-Akt ^Thr308、p-GSK3β ^Ser9、p-AMPK ^{Thr172）增加}）。由于 mTOR 通路是自噬的主要调节因子，因此测量了自噬蛋白。p-Beclin-1（BECN1）是 Beclin-1 调节的自噬（AMBRA1）中的一种自噬调节剂和激活分子，Beclin 的调节剂在自噬体形成（自噬的早期阶段）中发挥作用。自噬后期存在缺陷，即自噬体与溶酶体的融合，称为自噬通量，表现为自噬体标志物 LC3-II 与溶酶体抑制剂巴弗洛霉素缺乏增加。 70 天和 150 天的心脏。为了确定自噬在导致心脏重量增加中的作用，Pkd1 ^RC/RC用 2-脱氧葡萄糖 (2-DG) 或 Tat-Beclin1 肽处理，这些药物已知可诱导自噬。2-DG 治疗从 150 到 350 日龄，即心脏重量增加的时期，并没有减少增加的心脏重量。出乎意料的是，从 70 到 120 天龄的 Tat-Beclin 1 肽治疗导致心脏重量增加。总之，在Pkd1 ^RC/RC小鼠的早期，心脏中的自噬通量受到抑制。在老年小鼠中增加的 mTOR 信号与抑制自噬通量有关。在年轻和年老小鼠中，p-AMPK ^Thr172（一种已知的自噬诱导剂）都有大量增加。2-DG 治疗不影响心脏重量增加，Tat-Beclin1 肽增加心脏重量。