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

Li，Lingfei1,2,3; Feng，Yanhai2,3; Zhang，Junhui8; Zhang，Qiong2,3; Ren，Jun4,5; Sun，Cheng6; Li，Shujing7; Lei，Xia1; Luo，Gaoxing2,3; Hu，Jiongyu3,8; Huang，Yuesheng2,3,9

2022-12-01

10.1186/s12964-022-00883-7

Cell Communication and Signaling   Impact Factor & Quartile

1478-811X

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. [MediaObject not available: see fulltext.].

Apoptosis Diabetic nephropathy Epithelial-to-mesenchymal transition MAP4 Proteinuria

SCI

English

Corresponding

National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[82003323];

WOS:000832707700001

2-s2.0-85135138261

Scopus

1.Department of Dermatology,Daping Hospital,Third Military Medical University (Army Medical University),Chongqing,China
2.Institute of Burn Research,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
3.State Key Laboratory of Trauma,Burns and Combined Injury,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
4.Department of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital,Fudan University,Shanghai,200032,China
5.Department of Laboratory Medicine and Pathology,University of Washington,Seattle,98195,United States
6.Department of Ophthalmology,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
7.The Second Affiliated Hospital of Chongqing Medical University,Chongqing,China
8.Endocrinology Department,Southwest Hospital,Third Military Medical University (Army Medical University),Chongqing,China
9.Department of Wound Repair,Institute of Wound Repair and Regeneration Medicine,Southern University of Science and Technology Hospital,Southern University of Science and Technology School of Medicine,Shenzhen,China

Li，Lingfei,Feng，Yanhai,Zhang，Junhui,et al. Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy[J]. Cell Communication and Signaling,2022,20(1).

Li，Lingfei.,Feng，Yanhai.,Zhang，Junhui.,Zhang，Qiong.,Ren，Jun.,...&Huang，Yuesheng.(2022).Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy.Cell Communication and Signaling,20(1).

Li，Lingfei,et al."Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy".Cell Communication and Signaling 20.1(2022).