Ina Maria Schiessl1,2, Alexandra Grill3, Katharina Fremter3, Dominik Steppan3, Maj-Kristina Hellmuth3, Hayo Castrop3. 1. Institute of Physiology, University of Regensburg, Regensburg, Germany; and Ina.maria.schiessl@gmail.com. 2. Department of Physiology and Biophysics, University of Southern California, Los Angeles, California. 3. Institute of Physiology, University of Regensburg, Regensburg, Germany; and.
Abstract
BACKGROUND: 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-β (PDGFRβ) 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. METHODS: In mice with fluorescent protein expression in renal tubular cells and PDGFRβ-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 ex vivo histology to evaluate the cellular and molecular processes involved in tubular regeneration. RESULTS: 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 PDGFRβ-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFRβ-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFRβ-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFRβ impeded PDGFRβ-positive cell migration to the tubular injury site and compromised the recovery of tubular function. CONCLUSIONS: Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFRβ-mediated communication between the renal interstitium and the tubular system.
BACKGROUND: 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-β (PDGFRβ) 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. METHODS: In mice with fluorescent protein expression in renal tubular cells and PDGFRβ-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 ex vivo histology to evaluate the cellular and molecular processes involved in tubular regeneration. RESULTS: 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 PDGFRβ-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFRβ-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFRβ-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFRβ impeded PDGFRβ-positive cell migration to the tubular injury site and compromised the recovery of tubular function. CONCLUSIONS: Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFRβ-mediated communication between the renal interstitium and the tubular system.
Authors: Jennifer Hansson; Kjell Hultenby; Catharina Cramnert; Fredrik Pontén; Hannes Jansson; David Lindgren; Håkan Axelson; Martin E Johansson Journal: Hum Pathol Date: 2013-10-18 Impact factor: 3.466
Authors: James L Burford; Karie Villanueva; Lisa Lam; Anne Riquier-Brison; Matthias J Hackl; Jeffrey Pippin; Stuart J Shankland; János Peti-Peterdi Journal: J Clin Invest Date: 2014-04-08 Impact factor: 14.808
Authors: Friederike Kessel; Anne Steglich; Linda Hickmann; Ricardo Lira Martinez; Michael Gerlach; Maria Luisa S Sequeira-Lopez; R Ariel Gomez; Christian P M Hugo; Vladimir T Todorov Journal: Am J Physiol Renal Physiol Date: 2021-08-02