期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 26, 期 7, 页码 1513-1523出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2014040345
关键词
FSGS; homeostasis; autophagy; nephrotic syndrome; regulated necrosis
资金
- Deutsche Forschungsgemeinschaft [TH1836/1-2, AN372/11-2]
- European Union FP7-REGPOT-2010-1 EnVision Grant [264143]
- Federal Ministry of Education and Research
- Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania [03IS2061A]
- National Institutes of Health/National Institute on Deafness and Other Communication Disorders [P30-DC04665]
Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and invivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivation-related cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据