Pippin Jeffrey W, Kaverina Natalya V, Eng Diana G, Krofft Ronald D, Glenn Sean T, Duffield Jeremy S, Gross Kenneth W, Shankland Stuart J
Division of Nephrology, University of Washington, Seattle, Washington;
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York; and.
Am J Physiol Renal Physiol. 2015 Aug 15;309(4):F341-58. doi: 10.1152/ajprenal.00438.2014. Epub 2015 Jun 10.
Modified vascular smooth muscle cells of the kidney afferent arterioles have recently been shown to serve as progenitors for glomerular epithelial cells in response to glomerular injury. To determine whether such cells of renin lineage (CoRL) serve as progenitors for other cells in kidney disease characterized by both glomerular and tubulointerstitial injury, permanent genetic cell fate mapping of adult CoRL using Ren1cCreER × Rs-tdTomato-R reporter mice was performed. TdTomato-labeled CoRL were almost completely restricted to the juxtaglomerular compartment in healthy kidneys. Following 2 wk of antibody-mediated focal segmental glomerulosclerosis (FSGS) or 16 wk of ⅚ nephrectomy-induced chronic kidney diseases, tdTomato-mapped CoRL were identified in both interstitial and glomerular compartments. In the interstitium, PDGFβ receptor (R)-expressing cells significantly increased, and a portion of these expressed tdTomato. This was accompanied by a decrease in native pericyte number, but an increase in the number of tdTomato cells that coexpressed the pericyte markers PDGFβ-R and NG2. These cells surrounded vessels and coexpressed the pericyte markers CD73 and CD146, but not the endothelial marker ERG. Within glomeruli of reporter mice with the ⅚ nephrectomy model, a subset of labeled CoRL migrated to the glomerular tuft and coexpressed podocin and synaptopodin. By contrast, labeled CoRL were not detected in glomerular or interstitial compartments following uninephrectomy. These observations indicate that in addition to supplying new adult podocytes to glomeruli, CoRL have the capacity to become new adult pericytes in the setting of interstitial disease. We conclude that CoRL have the potential to function as progenitors for multiple adult cell types in kidney disease.
最近研究表明，肾入球小动脉中经过修饰的血管平滑肌细胞在肾小球损伤时可作为肾小球上皮细胞的祖细胞。为了确定肾素谱系细胞（CoRL）是否可作为以肾小球和肾小管间质损伤为特征的肾脏疾病中其他细胞的祖细胞，我们使用Ren1cCreER×Rs-tdTomato-R报告基因小鼠对成年CoRL进行了永久性遗传细胞命运图谱分析。在健康肾脏中，tdTomato标记的CoRL几乎完全局限于球旁器。在抗体介导的局灶节段性肾小球硬化（FSGS）模型中，经过2周诱导后，或者在5/6肾切除诱导的慢性肾脏疾病模型中，经过16周诱导后，在间质和肾小球区域均发现了tdTomato标记的CoRL。在间质中，表达血小板衍生生长因子β受体（PDGFRβ）的细胞显著增加，其中一部分细胞表达tdTomato。这伴随着天然周细胞数量的减少，但共表达周细胞标志物PDGFRβ和NG2的tdTomato阳性细胞数量增加。这些细胞围绕血管，并共表达周细胞标志物CD73和CD146，但不表达内皮细胞标志物ERG。在5/6肾切除模型的报告基因小鼠肾小球内，一部分标记的CoRL迁移至肾小球毛细血管袢，并共表达足突蛋白和突触足蛋白。相比之下，在单侧肾切除后的小鼠中，未在肾小球或间质区域检测到标记的CoRL。这些观察结果表明，除了为肾小球提供新的成年足细胞外，CoRL在间质疾病发生时还具有成为新的成年周细胞的能力。我们得出结论，CoRL有潜力在肾脏疾病中作为多种成年细胞类型的祖细胞发挥作用。
