期刊
EXPERIMENTAL CELL RESEARCH
卷 382, 期 2-3, 页码 -出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2019.06.008
关键词
Necroptosis; Podocyte injury; RIPK1; RIPK3; UCHL1
资金
- National Key Research & Develop Program of China (China) [2016YFC1305500]
- project of Shanghai Key Laboratory of Kidney and Blood Purification (China) [14DZ2260200]
Diabetic nephrology (DN) is attributed largely to the depletion of podocytes, which is closely associated to apoptosis. However, the complex mechanism of podocyte loss in DN pathogenesis remains unclear. Recently, necroptosis has emerged as an important cell death model in many pathological conditions, which is regulated through RIPK1/RIPK3 pathway. In addition, necroptosis was found to share several upstream signaling pathways with apoptosis. Therefore, it was speculated that both apoptosis and necroptosis may occur in podocytes during the process of podocyte injury in ON. Herein, necroptosis and apoptosis were shown to be involved in podocyte injury induced by high glucose (HG), both in vitro and in vivo, with a high level of positive signaling markers RIPK1 (298.4 +/- 17.35), cleaved caspase 3 (497.1 +/- 23.09), RIPK3 (108.4 +/- 14.92), and MLKL (470.4 +/- 15.73) than the control groups. Scaning electron microscopy examination revealed the morphological characteristics of necroptotic and apoptotic cells, which differed remarkably. z-VAD-fmk, a pan-inhibitor of apoptosis, could block apoptosis and enhance necroptosis. Furthermore, UCHL1 was found to play a major role in promoting podocyte necroptosis by regulating the ubiquitination state of the RIPK1/RIPK3 pathway. The halflife of RIPK1 and RIPK3 proteins reduced and the expression of RIPK1, RIPK3, and MLKL decreased significantly after the knockdown of UCHL1. It was shown that UCHL1 exerted a more regulatory response to necroptosis. These data suggested that necroptosis may have more effect on the loss of podocytes than apoptosis in DN with the regulation of UCHL1. Thus, inhibiting UCHL1 to downregulate the RIPK1/RIPK3 pathway may be a novel strategy to protect the podocytes in DN patients.
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