Cell Atavistic Transition: Paired Box 2 Re-Expression Occurs in Mature Tubular Epithelial Cells during Acute Kidney Injury and Is Regulated by Angiotensin II
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.
References
[1]
Kusch A, Hoff U, Bubalo G, Zhu Y, Fechner M, et al.. (2013) Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury. Acta Physiol (Oxf).
[2]
Maeshima A, Yamashita S, Nojima Y (2003) Identification of renal progenitor-like tubular cells that participate in the regeneration processes of the kidney. J Am Soc Nephrol 14: 3138–3146. doi: 10.1097/01.asn.0000098685.43700.28
[3]
Gupta S, Verfaillie C, Chmielewski D, Kren S, Eidman K, et al. (2006) Isolation and characterization of kidney-derived stem cells. J Am Soc Nephrol 17: 3028–3040. doi: 10.1681/asn.2006030275
[4]
Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, et al. (2005) Isolation of renal progenitor cells from adult human kidney. Am J Pathol 166: 545–555. doi: 10.1016/s0002-9440(10)62276-6
[5]
Humphreys BD, Czerniak S, DiRocco DP, Hasnain W, Cheema R, et al. (2011) Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci U S A 108: 9226–9231. doi: 10.1073/pnas.1100629108
[6]
Huang B, Pi L, Chen C, Yuan F, Zhou Q, et al. (2012) WT1 and Pax2 re-expression is required for epithelial-mesenchymal transition in 5/6 nephrectomized rats and cultured kidney tubular epithelial cells. Cells Tissues Organs 195: 296–312. doi: 10.1159/000327530
[7]
Jiang YS, Jiang T, Huang B, Chen PS, Ouyang J (2013) Epithelial-mesenchymal transition of renal tubules: Divergent processes of repairing in acute or chronic injury? Med Hypotheses 81: 73–75. doi: 10.1016/j.mehy.2013.03.020
[8]
Witzgall R, Brown D, Schwarz C, Bonventre JV (1994) Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 93: 2175–2188. doi: 10.1172/jci117214
[9]
Torban E, Goodyer P (1998) What PAX genes do in the kidney. Exp Nephrol 6: 7–11. doi: 10.1159/000020498
[10]
Batchelder CA, Lee CC, Matsell DG, Yoder MC, Tarantal AF (2009) Renal ontogeny in the rhesus monkey (Macaca mulatta) and directed differentiation of human embryonic stem cells towards kidney precursors. Differentiation 78: 45–56. doi: 10.1016/j.diff.2009.05.001
[11]
Torban E, Goodyer PR (1998) Effects of PAX2 expression in a human fetal kidney (HEK293) cell line. Biochim Biophys Acta 1401: 53–62. doi: 10.1016/s0167-4889(97)00119-5
[12]
Torres M, Gomez-Pardo E, Dressler GR, Gruss P (1995) Pax-2 controls multiple steps of urogenital development. Development 121: 4057–4065.
Dressler GR (1996) Pax-2, kidney development, and oncogenesis. Med Pediatr Oncol 27: 440–444. doi: 10.1002/(sici)1096-911x(199611)27:5<440::aid-mpo9>3.0.co;2-m
[15]
Efrati S, Berman S, Abu Hamad R, El Nakib R, Chanimov M, et al. (2012) Hyperglycaemia, inflammation, RAS activation: three culprits to blame for acute kidney injury emerging in healthy rats during general anaesthesia. Nephrology (Carlton) 17: 591–602. doi: 10.1111/j.1440-1797.2012.01638.x
[16]
Wolf G (2000) Angiotensin II as a mediator of tubulointerstitial injury. Nephrol Dial Transplant 15 Suppl 661–63. doi: 10.1093/ndt/15.suppl_6.61
[17]
Wolf G (2002) Angiotensin II and tubular development. Nephrol Dial Transplant 17: 48–51. doi: 10.1093/ndt/17.suppl_9.48
[18]
Zhang SL, Moini B, Ingelfinger JR (2004) Angiotensin II increases Pax-2 expression in fetal kidney cells via the AT2 receptor. J Am Soc Nephrol 15: 1452–1465. doi: 10.1097/01.asn.0000130567.76794.58
[19]
Lasaitiene D, Chen Y, Adams MA, Friberg P (2006) Further insights into the role of angiotensin II in kidney development. Clin Physiol Funct Imaging 26: 197–204. doi: 10.1111/j.1475-097x.2006.00676.x
[20]
Shanmugam S, Llorens-Cortes C, Clauser E, Corvol P, Gasc JM (1995) Expression of angiotensin II AT2 receptor mRNA during development of rat kidney and adrenal gland. Am J Physiol 268: F922–930. doi: 10.1038/ki.1995.156
[21]
Cao Z, Kelly DJ, Cox A, Casley D, Forbes JM, et al. (2000) Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int 58: 2437–2451. doi: 10.1046/j.1523-1755.2000.00427.x
[22]
Zhu YZ, Chimon GN, Zhu YC, Lu Q, Li B, et al. (2000) Expression of angiotensin II AT2 receptor in the acute phase of stroke in rats. Neuroreport 11: 1191–1194. doi: 10.1097/00001756-200004270-00009
[23]
Paller MS, Hoidal JR, Ferris TF (1984) Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 74: 1156–1164. doi: 10.1172/jci111524
[24]
Cai Q, Dmitrieva NI, Ferraris JD, Brooks HL, van Balkom BW, et al. (2005) Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance. Proc Natl Acad Sci U S A 102: 503–508. doi: 10.1073/pnas.0408840102
[25]
Maeshima A, Maeshima K, Nojima Y, Kojima I (2002) Involvement of Pax-2 in the action of activin A on tubular cell regeneration. J Am Soc Nephrol 13: 2850–2859. doi: 10.1097/01.asn.0000035086.93977.e9
