Tang Xiaoshan, Sun Manqing, Shen Qian, Rao Jia, Yang Xue, Fang Ye, Xiang Tianchao, Xue Shanshan, Sun Lei, Xu Hong
Department of Nephrology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China.
Front Cell Dev Biol. 2022 Oct 18;10:929556. doi: 10.3389/fcell.2022.929556. eCollection 2022.
Adverse intrauterine and early postnatal environment cause reduced nephron endowment and subsequent hypertension, chronic kidney disease (CKD). Exploring modifiable approaches is particularly important to alleviate the global burden of CKD. Enhanced glomerular progenitor cell apoptosis is a major contributor to renal developmental programming. The differentially expressed protein perlecan, which we previously identified using proteomics, is an important extracellular matrix glycoprotein, and its domain V (endorepellin) can inhibit apoptosis through a paracrine form. In explanted mice embryonic metanephros, we found that endorepellin can rescue glomeruli-deficit phenotype resulting from malnutrition, and this protective effect was also verified using a renal developmental programming model which was given a low-protein diet during pregnancy. We further demonstrated that endorepellin significantly inhibited glomerular progenitor cell apoptosis which activates ERK1/2 phosphorylation. Our results show that endorepellin rescues the nephron number reduction in renal developmental programming, possibly through the inhibition of progenitor cell apoptosis the ERK1/2 pathway.
子宫内及出生后早期的不良环境会导致肾单位数量减少，并引发后续的高血压和慢性肾脏病（CKD）。探索可改变的方法对于减轻全球CKD负担尤为重要。肾小球祖细胞凋亡增加是肾脏发育编程的主要原因。我们之前通过蛋白质组学鉴定出的差异表达蛋白核心蛋白聚糖是一种重要的细胞外基质糖蛋白，其结构域V（内源性趋化素）可通过旁分泌形式抑制细胞凋亡。在体外培养的小鼠胚胎后肾中，我们发现内源性趋化素可挽救营养不良导致的肾小球缺陷表型，并且在孕期给予低蛋白饮食的肾脏发育编程模型中也验证了这种保护作用。我们进一步证明，内源性趋化素可显著抑制肾小球祖细胞凋亡并激活ERK1/2磷酸化。我们的结果表明，内源性趋化素可能通过抑制祖细胞凋亡和ERK1/2途径来挽救肾脏发育编程过程中的肾单位数量减少。
