Origin of regenerating tubular cells after acute kidney injury

Abstract

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.