Repair of injured proximal tubule does not involve specialized progenitors

Abstract

Recently we have established that the kidney tubular epithelium is repaired by surviving epithelial cells. It is not known, however, whether a population of intratubular adult progenitor cells are responsible for this epithelial repair after acute kidney injury. In this study, we used an unbiased DNA analog-based approach that does not rely on candidate markers to track multiple rounds of cell division in vivo. In the proximal tubule, robust thymidine analog incorporation was observed postinjury. Cell division was stochastic and enriched among cells that were injured and dedifferentiated. There was no evidence for the presence of a population of specialized progenitors that repeatedly divide in response to injury. Instead, these results indicate that after injury, new epithelial cells arise from self-duplication of surviving cells, most of which are injured. Because the renal papilla contains DNA label-retaining cells and has been proposed as a stem cell niche, we examined the proliferative behavior of these putative progenitors after ischemiareperfusion injury. Although label-retaining cells in the renal papilla diminished with time after ischemia-reperfusion injury, they neither proliferated nor migrated to the outer medulla or cortex. Thus, nonlethally injured cells repopulate the kidney epithelium after injury in the absence of any specialized progenitor cell population.

Characterization of Renal Progenitors Committed Toward Tubular Lineage and Their Regenerative Potential in Renal Tubular Injury

“…However, during AKI, repair of epithelial cells mostly depends on cells directly derived from the migration and proliferation of adjacent tubular epithelial cells [1,2]. In addition, a recent study in rodents demonstrated that proliferation of regenerating tubular epithelium following acute ischemic injury is stochastically distributed among surviving tubular cells [25]. However, the existence of a scattered population of CD133þCD24þ tubular-committed progenitors that is highly resistant to death induced by toxic agents is consistent with this observation.…”

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

“…Remarkably, during AKI, the normally quiescent renal tubular cells reenter the cell cycle (29)(30)(31)(32)(33)(34), and blocking cell-cycle progression can reduce renal injury (28). Here, we provide evidence that the CDK4/6 pathway is activated early during AKI and demonstrate significant protective effects of CDK4/6 inhibitors in animal models of cisplatin-induced AKI.…”

“…However, the major etiology of AKI is renal tubular cell death caused by ischemia, infections, or drug-induced toxicities (44)(45)(46)(47). During AKI, along with cell death, cell-cycle activation is initiated in the normally quiescent renal tubular cells (29)(30)(31)(32)(33)(34). It is believed that this proliferative response may contribute to tissue regeneration (28,32,33,38), although this notion has been challenged recently (48).…”

“…During AKI, along with cell death, cell-cycle activation is initiated in the normally quiescent renal tubular cells (29)(30)(31)(32)(33)(34). It is believed that this proliferative response may contribute to tissue regeneration (28,32,33,38), although this notion has been challenged recently (48). These issues notwithstanding, it is clear that a significant fraction of renal tubular cells enter the cell cycle during AKI (32,34) and that blocking or delaying cell-cycle entry has protective effects (28).…”

“…It is believed that this proliferative response may contribute to tissue regeneration (28,32,33,38), although this notion has been challenged recently (48). These issues notwithstanding, it is clear that a significant fraction of renal tubular cells enter the cell cycle during AKI (32,34) and that blocking or delaying cell-cycle entry has protective effects (28). Studies with both genetic mouse models and pharmacological inhibitors have shown that inducing cell-cycle arrest by overexpression of p21 or treatment with CDK2 inhibitors prevents AKI, whereas knockdown of p21 increases renal tissue damage (28,29).…”