Myeloid-derived growth factor deficiency exacerbates mitotic catastrophe of podocytes in glomerular disease

足细胞 肾小球硬化 生物 局灶节段性肾小球硬化 肾脏疾病 有丝分裂 核分裂突变 内科学 内分泌学 癌症研究 细胞生物学 医学 肾小球肾炎 细胞周期 蛋白尿 细胞 遗传学
作者
Ping Zhan,Yang Zhang,Weichen Shi,Xiaohan Liu,Zhe Qiao,Ziying Wang,Xiaojie Wang,Jichao Wu,Wei Tang,Yu Sun,Yan Zhang,Junhui Zhen,Jin Shang,Min Liu,Fan Yi
出处
期刊:Kidney International [Elsevier BV]
卷期号:102 (3): 546-559 被引量:35
标识
DOI:10.1016/j.kint.2022.04.027
摘要

Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering 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 indicate that MYDGF may be an attractive therapeutic target for glomerular disease. Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering 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 indicate that MYDGF may be an attractive therapeutic target for glomerular disease. In This IssueKidney InternationalVol. 102Issue 3PreviewGorski et al. meta-analyzed genome-wide association studies that covered 343,339 individuals to uncover top-priority genes responsible for progressive decline in estimated glomerular filtration rate (eGFR). This analysis identified 12 variants across 11 loci significant for annual decline in eGFR, and 9 variants that were important in analyses adjusted or unadjusted for baseline glomerular filtration rate. The effects of these variants were magnified 2- to 4-fold in patients with diabetes or chronic kidney disease (CKD) at baseline. Full-Text PDF
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