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微管相关蛋白 4 磷酸化诱导足细胞上皮-间质转化导致糖尿病肾病蛋白尿。

Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy.

机构信息

Department of Dermatology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

出版信息

Cell Commun Signal. 2022 Jul 28;20(1):115. doi: 10.1186/s12964-022-00883-7.

DOI:10.1186/s12964-022-00883-7
PMID:35902952
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9331595/
Abstract

BACKGROUND

Diabetic nephropathy (DN) involves various structural and functional changes because of chronic glycemic assault and kidney failure. Proteinuria is an early clinical manifestation of DN, but the associated pathogenesis remains elusive. This study aimed to investigate the role of microtubule associated protein 4 (MAP4) phosphorylation (p-MAP4) in proteinuria in DN and its possible mechanisms.

METHODS

In this study, the urine samples of diabetic patients and kidney tissues of streptozotocin (STZ)-induced diabetic mice were obtained to detect changes of p-MAP4. A murine model of hyperphosphorylated MAP4 was established to examine the effect of MAP4 phosphorylation in DN. Podocyte was applied to explore changes of kidney phenotypes and potential mechanisms with multiple methods.

RESULTS

Our results demonstrated elevated content of p-MAP4 in diabetic patients' urine samples, and increased kidney p-MAP4 in streptozocin (STZ)-induced diabetic mice. Moreover, p-MAP4 triggered proteinuria with aging in mice, and induced epithelial-to-mesenchymal transition (EMT) and apoptosis in podocytes. Additionally, p-MAP4 mice were much more susceptible to STZ treatment and showed robust DN pathology as compared to wild-type mice. In vitro study revealed high glucose (HG) triggered elevation of p-MAP4, rearrangement of microtubules and F-actin filaments with enhanced cell permeability, accompanied with dedifferentiation and apoptosis of podocytes. These effects were significantly reinforced by MAP4 hyperphosphorylation, and were rectified by MAP4 dephosphorylation. Notably, pretreatment of p38/MAPK inhibitor SB203580 reinstated all HG-induced pathological alterations.

CONCLUSIONS

The findings indicated a novel role for p-MAP4 in causing proteinuria in DN. Our results indicated the therapeutic potential of MAP4 in protecting against proteinuria and related diseases. Video Abstract.

摘要

背景

糖尿病肾病（DN）涉及各种结构和功能变化，由于慢性血糖攻击和肾功能衰竭。蛋白尿是 DN 的早期临床表现，但相关发病机制仍不清楚。本研究旨在探讨微管相关蛋白 4（MAP4）磷酸化（p-MAP4）在 DN 蛋白尿中的作用及其可能的机制。

方法

本研究中，获取糖尿病患者的尿样和链脲佐菌素（STZ）诱导的糖尿病小鼠的肾脏组织，以检测 p-MAP4 的变化。建立高磷酸化 MAP4 的小鼠模型，以检查 MAP4 磷酸化在 DN 中的作用。应用足细胞，通过多种方法探索肾脏表型变化及其潜在机制。

结果

我们的结果表明，糖尿病患者尿样中 p-MAP4 含量升高，STZ 诱导的糖尿病小鼠肾脏中 p-MAP4 增加。此外，p-MAP4 随着小鼠年龄的增长引发蛋白尿，并诱导足细胞发生上皮-间充质转化（EMT）和凋亡。此外，与野生型小鼠相比，p-MAP4 小鼠对 STZ 处理更敏感，表现出更强的 DN 病理学。体外研究表明，高葡萄糖（HG）可触发 p-MAP4 升高，微管和 F-肌动蛋白丝重排，增加细胞通透性，同时伴随足细胞去分化和凋亡。MAP4 过度磷酸化显著增强了这些效应，而 MAP4 去磷酸化则纠正了这些效应。值得注意的是，p38/MAPK 抑制剂 SB203580 的预处理恢复了所有 HG 诱导的病理改变。

结论

这些发现表明 p-MAP4 在引起 DN 蛋白尿中具有新的作用。我们的研究结果表明，MAP4 在预防蛋白尿和相关疾病方面具有治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/988aefe6d571/12964_2022_883_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/988aefe6d571/12964_2022_883_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/3046dcedd653/12964_2022_883_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/84ce0c7c6c84/12964_2022_883_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/5215dc68d7a1/12964_2022_883_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/a5ed48d91c6f/12964_2022_883_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/c3bc0bea6fca/12964_2022_883_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6580/9331595/988aefe6d571/12964_2022_883_Fig9_HTML.jpg

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