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

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

Cell communication and signaling : CCS (2022-07-29)
Lingfei Li, Yanhai Feng, Junhui Zhang, Qiong Zhang, Jun Ren, Cheng Sun, Shujing Li, Xia Lei, Gaoxing Luo, Jiongyu Hu, Yuesheng Huang
초록

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. 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. 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. 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.

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Sigma-Aldrich
In Vivo EdU Click Kit 488, sufficient for 100 assays
Roche
In Situ Cell Death Detection Kit, Fluorescein, sufficient for ≤50 tests, suitable for detection
Sigma-Aldrich
SB 203580, SB 203580, CAS 152121-47-6, is a highly specific, potent, cell-permeable, selective, reversible, and ATP-competitive inhibitor of p38 MAP kinase (IC₅₀ = 34 nM in vitro, 600 nM in cells).