Involvement of Pax-2 in the action of activin A on tubular cell regeneration.
It has been recently shown that in ischemic rat kidneys activin A is induced in tubular cells and inhibits their regeneration. The present study was conducted to further investigate the action of activin A in tubular cells during regeneration. Among genes thought to be critical for kidney development, Pax-2 was upregulated in tubular cells during regeneration after renal ischemia. Pax-2 protein was localized in nuclei of tubular and interstitial cells, some of which co-expressed a mesenchymal cell marker, vimentin, suggesting that a population of Pax-2-positive cells have properties of immature progenitor-like tubular cells. The Pax-2-expressing cells co-expressed a cell proliferation marker, BrdU, activin A, and the type II activin receptor. Activin A modulated growth of BrdU/Pax-2 double-positive cells since an administration of follistatin increased; conversely, exogenous activin A decreased the number of BrdU/Pax-2 double-positive cells after renal ischemia. Activin A also reduced the expression of Pax-2 in cultured metanephroi. A proximal tubular cell line, LLC-PK(1) cells, was used to further study the mode of action of activin A. The expression of Pax-2 was not detected in quiescent LLC-PK(1) cells, but it was markedly increased when growth was stimulated. Under this condition, activin A significantly inhibited DNA synthesis and reduced the expression of Pax-2 in LLC-PK(1) cells. In contrast, blockade of the activin signaling by overexpressing dominantly negative mutant receptor enhanced the expression level of Pax-2 in LLC-PK(1) cells and induced an immature phenotype. These results suggest that activin A regulates tubular cell growth and differentiation by modulating the expression of Pax-2 during regeneration.
Maeshima
Akito
A
Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Maeshima
Kyoko
K
Nojima
Yoshihisa
Y
Kojima
Itaru
I
D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D038681:Follistatin / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D028322:Inhibin-beta Subunits / Q000494:pharmacology / Q000502:physiology*; D007511:Ischemia / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000503:physiopathology*; D018374:LLC-PK1 Cells; D008297:Male; D051762:PAX2 Transcription Factor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000502:physiology*; D012079:Renal Circulation; D013552:Swine; D014018:Tissue Distribution; D014157:Transcription Factors / Q000502:physiology*; D014746:Vimentin / Q000378:metabolism
D004268:DNA-Binding Proteins; D038681:Follistatin; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D014746:Vimentin; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D030301:Activin Receptors, Type II