期刊
KIDNEY INTERNATIONAL
卷 102, 期 3, 页码 546-559出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.04.027
关键词
cell death; glomerular disease; mitotic catastrophe; MYDGF; podocytes
资金
- National Nature Science Foundation of China [81800645, 91949202, 82090024, 82090021, 81800643, 81900621, 81873614]
- National Key R&D Program of China [2020YFC2005000]
- Shandong Provincial Natural Science Foundation, China [ZR2019BH030, ZR2019ZD40]
- China Postdoctoral Science Foundation [2018M640634]
- Fundamental Research Funds of Shandong University [21510078614058]
- Future Scholar Program of Shandong University [21510089964238]
MYDGF plays an important role in podocytes by protecting against mitotic catastrophe and regulating the expression of the transcription factor RUNX2. Its reduction in glomeruli from patients with glomerular disease is correlated with glomerular filtration rate, serum creatinine, and podocyte loss.
Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Reentering the mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role in the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of Mydgf in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in the S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates some MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies target for glomerular disease.
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