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Vitamin D-VDR (vitamin D receptor) regulates defective autophagy in renal tubular epithelial cell in streptozotocin-induced diabetic mice via the AMPK pathway
Autophagy ( IF 13.3 ) Pub Date : 2021-08-25 , DOI: 10.1080/15548627.2021.1962681
Aimei Li 1 , Bin Yi 1 , Hailong Han 2, 3 , Shikun Yang 1 , Zhaoxin Hu 1 , Li Zheng 1 , Jianwen Wang 1 , Qin Liao 4 , Hao Zhang 1
Affiliation  

ABSTRACT

Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in vdr knockout (vdr-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (Vdr-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or Vdr-OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in vdr-KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in vdr-KO mice and could be partially restored by paricalcitol or Vdr-OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKβ inhibition, but not by STK11/LKB1 knockout. Meanwhile, paricalcitol rescued the decreased Ca2+ concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca2+-CAMKK2-AMPK pathway in renal tubular epithelial cells.

Abbreviations: ACTB/β-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKβ: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type



中文翻译:

维生素 D-VDR(维生素 D 受体)通过 AMPK 途径调节链脲佐菌素诱导的糖尿病小鼠肾小管上皮细胞自噬缺陷

摘要

糖尿病肾病(DN)已成为终末期肾病的主要原因,自噬障碍与DN的发病机制有关。我们之前的研究发现,维生素 D(VD)和 VDR(维生素 D 受体)通过抑制炎症和纤维化发挥肾脏保护作用。然而,VD-VDR 是否调节 DN 中的自噬障碍仍不清楚。在这项研究中,我们在vdr敲除 ( vdr -KO) 小鼠中建立了链脲佐菌素 (STZ) 诱导的糖尿病模型,并在肾近端肾小管上皮细胞 ( Vdr -OE) 小鼠中特异性过表达 VDR。我们的结果表明,帕立骨化醇(一种活化的维生素 D 类似物)或Vdr-OE 可以减轻 STZ 诱导的 ALB(白蛋白)排泄、肾小管损伤和炎症,而这些在vdr -KO 小鼠中恶化。在 STZ 小鼠的肾脏中观察到有缺陷的自噬,这在vdr -KO 小鼠中更为明显,并且可以通过帕立骨化醇或Vdr -OE 部分恢复。在高糖诱导的 HK-2 细胞中,观察到自噬缺陷和 PRKAA1/AMPK 磷酸化降低,帕立骨化醇可以以 VDR 依赖性方式部分恢复。AMPK 抑制剂消除了帕立骨化醇诱导的自噬激活,AMPK 激活剂恢复了高糖诱导的 HK-2 细胞中缺陷的自噬。此外,帕立骨化醇介导的 AMPK 活化被 CAMKK2/CaMKKβ 抑制所消除,但不能被STK11/LKB1淘汰赛。同时,帕立骨化醇挽救了由高糖引起的Ca 2+浓度降低。总之,VD-VDR可以恢复STZ诱导的糖尿病小鼠肾脏自噬缺陷,这可能是由于激活了肾小管上皮细胞中Ca 2+ -CAMKK2-AMPK通路。

缩写: ACTB/β-actin:肌动蛋白β;AGE:晚期糖基化终产物;AMPK:AMP 活化蛋白激酶;CAMKK2/CaMKKβ:钙钙调蛋白依赖性蛋白激酶激酶 2;CQ:氯喹;DN:糖尿病肾病;HG : 高水平的葡萄糖;KO: 敲除;LG: 低水平的葡萄糖;MAP1LC3/LC3: 微管相关蛋白 1 轻链 3;NOD2: 含有 2 的核苷酸结合寡聚结构域;OE: 过表达;PAS: 高碘酸席夫; Pari:帕立骨化醇;PTECs:近端肾小管上皮细胞;RT:室温;SQSTM1/p62:隔离体 1;STK11/LKB1:丝氨酸/苏氨酸激酶 11;STZ:链脲佐菌素;TEM:透射电镜;VD:维生素 D;VDR : 维生素 D 受体;WT: 野生型

更新日期:2021-08-25
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