Protective Role of Tangshen Formula on the Progression of Renal Damage in db/db Mice by TRPC6/Talin1 Pathway in Podocytes.
Protective Role of Tangshen Formula on the Progression of Renal Damage in db/db Mice by TRPC6/Talin1 Pathway in Podocytes.
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DOI：
10.1155/2020/3634974
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发表时间：
2020
影响因子：
4.3
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Wang Q;Tian X;Zhou W;Wang Y;Zhao H;Li J;Zhou X;Zhang H;Zhao T;Li P
糖肾方(TSF)是一种中药方剂，已有报道用于缓解糖尿病肾病(DKD)患者的蛋白尿和保护肾功能。然而，对其改善蛋白尿的机制知之甚少。足细胞-基质黏附的失调在包括DKD在内的蛋白尿肾脏疾病的发生和发展中起着重要作用。本研究采用体内2型DKD db/db小鼠模型和晚期糖基化终产物(AGEs)刺激的原代小鼠足细胞模型，研究了TSF对足细胞的保护作用机制。结果表明，TSF治疗能明显减轻db/db小鼠足细胞数量减少和足突消失，减少蛋白尿，保护肾功能。Db/db小鼠足细胞瞬时受体电位规范通道6(TRPC6)的表达显著增加，talin1的表达显著降低。AGEs刺激的原代小鼠足细胞结果显示，细胞迁移和肌动蛋白-细胞骨架重排增加。此外，AGEs刺激的原代小鼠足细胞表现出依赖TRPC6的钙内流增加，Talin 1丢失，活化T细胞核因子(NFATC)2易位。TSF治疗后，这些由AGEs刺激的小鼠原代足细胞的这种失调明显减轻。TRPC6激动剂1-油酰基-2-乙酰基甘油(OAG)可阻断TSF对足细胞-基质黏附的保护作用。结论：TSF可保护足细胞免受损伤，减少DKD时的蛋白尿，其机制可能与调节足细胞内TRPC6/Talin1通路有关。
Tangshen Formula (TSF) is a Chinese Medicine formula that has been reported to alleviate proteinuria and protect renal function in humans and animals with diabetic kidney disease (DKD). However, little is known about its mechanism in improving proteinuria. The dysregulation of podocyte cell-matrix adhesion has been demonstrated to play an important role in the pathogenesis and progression of proteinuric kidney diseases including DKD. In the present study, the underlying protective mechanism of TSF on podocytes was investigated using the murine model of type 2 DKD db/db mice in vivo and advanced glycation end products (AGEs)-stimulated primary mice podocytes in vitro. Results revealed that TSF treatment could significantly mitigate reduction of podocyte numbers and foot process effacement, reduce proteinuria, and protect renal function in db/db mice. There was a significant increase in expression of transient receptor potential canonical channel 6 (TRPC6) and a decrease in expression of talin1 in podocytes of db/db mice. The results of AGEs-stimulated primary mice podocytes showed increased cell migration and actin-cytoskeleton rearrangement. Moreover, primary mice podocytes stimulated by AGEs displayed an increase in TRPC6-dependent Ca2+ influx, a loss of talin1, and translocation of nuclear factor of activated T cell (NFATC) 2. These dysregulations in mice primary podocytes stimulated by AGEs could be significantly attenuated after TSF treatment. 1-Oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, blocked the protective role of TSF on podocyte cell-matrix adherence. In conclusion, TSF could protect podocytes from injury and reduce proteinuria in DKD, which may be mediated by the regulation of the TRPC6/Talin1 pathway in podocytes.
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DOI：
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