Origin of regenerating tubular cells after acute kidney injury.
Acute kidney injury (AKI) is associated with high morbidity and mortality. Recent genetic fate mapping studies demonstrated that recovery from AKI occurs from intrinsic tubular cells. It is unresolved whether these intrinsic cells (so-called "scattered tubular cells") represent fixed progenitor cells or whether recovery involves any surviving tubular cell. Here, we show that the doxycycline-inducible parietal epithelial cell (PEC)-specific PEC-reverse-tetracycline transactivator (rtTA) transgenic mouse also efficiently labels the scattered tubular cell population. Proximal tubular cells labeled by the PEC-rtTA mouse coexpressed markers for scattered tubular cells (kidney injury molecule 1, annexin A3, src-suppressed C-kinase substrate, and CD44) and showed a higher proliferative index. The PEC-rtTA mouse labeled more tubular cells upon different tubular injuries but was independent of cellular proliferation as determined in physiological growth of the kidney. To resolve whether scattered tubular cells are fixed progenitors, cells were irreversibly labeled before ischemia reperfusion injury (genetic cell fate mapping). During recovery, the frequency of labeled tubular cells remained constant, arguing against a fixed progenitor population. In contrast, when genetic labeling was induced during ischemic injury and subsequent recovery, the number of labeled cells increased significantly, indicating that scattered tubular cells arise from any surviving tubular cell. In summary, scattered tubular cells do not represent a fixed progenitor population but rather a phenotype that can be adopted by almost any proximal tubular cell upon injury. Understanding and modulating these phenotypic changes using the PEC-rtTA mouse may lead to more specific therapies in AKI.
Departments of Internal Medicine II, Nephrology and Immunology, and Internal Medicine III, Gastroenterology and Endocrinology, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University Hospital, D-52074 Aachen, Germany.
Katja
K
Berger
Jörg-Martin
JM
Bangen
Linda
L
Hammerich
Christian
C
Liedtke
Jürgen
J
Floege
Bart
B
Smeets
Marcus Johannes
MJ
Moeller
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D007684:Kidney Tubules / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology; D019076:Transgenes
cell fate tracking; lineage tracing; regeneration; stem cells