Abstract
The regeneration of tubular epithelial cells (TECs) after acute kidney injury (AKI) is crucial for the recovery of renal structure and function. The mechanism by which quiescent TECs re-obtain a potential to regenerate remains unknown. In this study, we observed a transient re-expression of embryonic gene Paired box 2 (Pax2) in adult rat TECs in vivo during ischemia-reperfusion induced AKI and most Pax2 positive TECs co-expressed kidney injury molecule-1 (KIM-1), a tubular injury marker. The re-expression of Pax2 was accompanied by increased levels of intrarenal Angiotensin II, which is a crucial injury factor of AKI. Furthermore, we also found a temporary re-expression of Pax2 in NRK-52E cells under the stimulation of Angiotensin II. This stimulatory effect could be blocked by PD123319 (Angiotensin II type 2 receptor (AT2R) inhibitor) and AG490 (Janus Kinase 2 (JAK2) inhibitor). As Pax2 is essential for the phenotypic conversion from mesenchymal stem cells to TECs during kidney development, we proposed that the re-expression of Pax2 in mature TECs may be an indicator of “atavistic” transition which mimics but reverses the processes of development of TECs. This could be proved by that a progenitor marker, CD24, was also found to be transiently expressed shortly after the expression of Pax2 in NRK-52E cells stimulated with Angiotensin II. The expression of CD24 was also suppressed by PD123319 and AG490. Moreover, knockdown of Pax2 by RNA interference could significantly reduce the expression of CD24 in NRK-52E cells stimulated with Angiotension II. Those findings suggest that mature TECs can trans-differentiate into progenitor-like cells by “atavistic transition”, which may participate in the recovery of tissue structure and Pax2 may play a pivotal role in this process. That might have important implications for further understanding of tubular regeneration after injury.
Highlights
Acute kidney injury (AKI) is a common and severe clinical problem
Our previous study demonstrated that tubular epithelial cells (TECs) could be induced to temporarily re-express embryonic gene Paired box 2 (Pax2) during chronic kidney injury, which indicated that TECs could transform into an immature cell phenotype and participate in kidney repair during chronic kidney injury [6]
We demonstrated that Pax2 was re-expressed in TECs during AKI in vivo, and we found that Pax2 and a stem/progenitor cell marker, CD24, were temporarily reexpressed in NRK-52E cells stimulated with Angiotensin II (Ang II) in vitro
Summary
Acute kidney injury (AKI) is a common and severe clinical problem. The recovery of renal function after AKI depends on the recovery of renal tubular epithelium[1], but the mechanism of tubular epithelial reconstruction remains unclear. It has been proposed that surviving tubular epithelial cells (TECs) re-enter cell cycle and replace damaged TECs by proliferating, but the mechanism by which quiescent TECs regain the potential to regenerate is still unknown. This model has been challenged by recent studies which suggest a role for stem/ progenitor cells in kidney repair. We proposed that a similar "atavistic" phenotype transition might occur during AKI [7] This notion is supported by the finding that a mesenchymal cell marker, vimentin, could be expressed in tubular epithelium during the recovery stage of AKI [8]
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