Institute of Physiology, University of Regensburg, Regensburg, Germany; and
Department of Physiology and Biophysics, University of Southern California, Los Angeles, California.
J Am Soc Nephrol. 2018 May;29(5):1383-1396. doi: 10.1681/ASN.2017101069. Epub 2018 Feb 23.
The kidney is considered to be a structurally stable organ with limited baseline cellular turnover. Nevertheless, single cells must be constantly replaced to conserve the functional integrity of the organ. PDGF chain B (PDGF-BB) signaling through fibroblast PDGF receptor- (PDGFR) contributes to interstitial-epithelial cell communication and facilitates regenerative functions in several organs. However, the potential role of interstitial cells in renal tubular regeneration has not been examined.
In mice with fluorescent protein expression in renal tubular cells and PDGFR-positive interstitial cells, we ablated single tubular cells by high laser exposure. We then used serial intravital multiphoton microscopy with subsequent three-dimensional reconstruction and histology to evaluate the cellular and molecular processes involved in tubular regeneration.
Single-tubular cell ablation caused the migration and division of dedifferentiated tubular epithelial cells that preceded tubular regeneration. Moreover, tubular cell ablation caused immediate calcium responses in adjacent PDGFR-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFR-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFR-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFR impeded PDGFR-positive cell migration to the tubular injury site and compromised the recovery of tubular function.
Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFR-mediated communication between the renal interstitium and the tubular system.
肾脏被认为是一种结构稳定的器官，其基底细胞的更替有限。然而，为了保持器官的功能完整性，单个细胞必须不断被替换。成纤维细胞 PDGF 受体（PDGFR）通过 PDGF 链 B（PDGF-BB）信号传导，有助于间质-上皮细胞的通讯，并促进几个器官的再生功能。然而，间充质细胞在肾小管再生中的潜在作用尚未被研究过。
在荧光蛋白在肾小管细胞和 PDGFR 阳性间质细胞中表达的小鼠中，我们通过高激光暴露来消融单个肾小管细胞。然后，我们使用连续的活体多光子显微镜，随后进行三维重建和组织学检查，以评估涉及肾小管再生的细胞和分子过程。
单个肾小管细胞消融导致去分化的肾小管上皮细胞的迁移和分裂，这先于肾小管再生。此外，肾小管细胞消融导致相邻 PDGFR 阳性间质细胞立即出现钙反应，并迅速向损伤部位迁移。这些 PDGFR 阳性细胞在肾小管细胞去分化之前包围受伤的上皮细胞，随后这些 PDGFR 阳性细胞的撤回与肾小管细胞再分化的迹象相关。腹腔内给予 trapidil 以阻断 PDGFR 会阻碍 PDGFR 阳性细胞向肾小管损伤部位迁移，并损害肾小管功能的恢复。
在依赖于 PDGFR 介导的肾间质与肾小管系统之间通讯的过程中，被消融的肾小管细胞完全由驻留的肾小管细胞增殖所取代。
