Role of pyruvate kinase M2-mediated metabolic reprogramming during podocyte differentiation

作者：Qi Yuan, Jiao Miao, Qianqian Yang, Li Fang, Yi Fang, Hao Ding, Yang Zhou, Lei Jiang, Chunsun Dai, Ke Zen, Qi Sun, Junwei Yang · 发表于：Cell Death and Disease · 年份：2020 · DOI：10.1038/s41419-020-2481-5 · 被引用次数：97 · 研究领域：Renal Diseases and Glomerulopathies、Genetic and Kidney Cyst Diseases、Renal and related cancers

Podocytes, a type of highly specialized epithelial cells, require substantial levels of energy to maintain glomerular integrity and function, but little is known on the regulation of podocytes' energetics. Lack of metabolic analysis during podocyte development led us to explore the distribution of mitochondrial oxidative phosphorylation and glycolysis, the two major pathways of cell metabolism, in cultured podocytes during in vitro differentiation. Unexpectedly, we observed a stronger glycolytic profile, accompanied by an increased mitochondrial complexity in differentiated podocytes, indicating that mature podocytes boost both glycolysis and mitochondrial metabolism to meet their augmented energy demands. In addition, we found a shift of predominant energy source from anaerobic glycolysis in immature podocyte to oxidative phosphorylation during the differentiation process. Furthermore, we identified a crucial metabolic regulator for podocyte development, pyruvate kinase M2. Pkm2-knockdown podocytes showed dramatic reduction of energy metabolism, resulting in defects of cell differentiation. Meanwhile, podocyte-specific Pkm2-knockout (KO) mice developed worse albuminuria and podocyte injury after adriamycin treatment. We identified mammalian target of rapamycin (mTOR) as a critical regulator of PKM2 during podocyte development. Pharmacological inhibition of mTOR potently abrogated PKM2 expression and disrupted cell differentiation, indicating the existence of metabolic checkp...