Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration

Abstract

Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent ‘normal’ proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive – indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo – arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration.

Origin of regenerating tubular cells after acute kidney injury

“…Our first major finding is that the inducible PEC-rtTA transgenic mouse labels STCs besides PECs but not other adjacent epithelial cells (i.e., podocytes or all remaining proximal tubular cells). This is consistent with previous proposals and data (12,15,17) that STCs express almost the same marker proteins as PECs, which are not shared by normal tubular cells in human kidney, suggesting a common transcriptional program in STCs and PECs. More than 80% of KIM-1-positive proximal tubular cells were also labeled by the PEC-rtTA mouse, and these cells consistently showed a higher proliferative index in vivo, which are characteristic features of STCs (11,12,17).…”

“…We later confirmed that nearly all marker proteins (45 of 49) that we found to be expressed by STCs were also expressed by PECs (12). This finding triggered us to use our Significance Acute kidney injury (AKI) is a common and significant clinical problem for which no specific therapy has been developed.…”

“…They can be found throughout the mammalian tubule in a scattered fashion. Phenotypically, these cells show signs of dedifferentiation and express marker proteins, which are also expressed by other stem or progenitor cells or in renal development (11,12). In contrast to stem cells, progenitor cells show a limited proliferative capacity, but both terms are often used synonymously.…”

“…Kidney injury molecule 1 (KIM-1) is expressed by proximal tubular cells showing the STC phenotype (12,17). To determine whether the PEC-rtTA transgenic mouse indeed preferentially labels STCs, kidneys were quadruple stained for Hoechst (labels all nuclei), AQP1 (proximal tubular cells), KIM-1 (marker of STCs), and EGFP-histone (labeled by the PEC-rtTA mouse) after I/R injury ( Fig.…”

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

“…Second, in a previous study we detected ANXA3 in a specific population of proximal tubular cells of the kidney, the so-called scattered tubular cells. 19,20 Scattered tubular cells express similar proteins as PECs. In the present study, we found that within the glomerulus ANXA3 was expressed exclusively by PECs and infiltrating leukocytes 21 ( Figure 7D).…”