Abstract
PHF14 is a newly identified regulator of mesenchyme growth in embryonic tissues. Previous studies have shown that phf14-null mutants die just after birth due to interstitial tissue hyperplasia in major organs, including the kidneys. The aim of this study was to investigate PHF14 function in renal fibrosis. By studying the chronic kidney injury mouse model, we found that PHF14 was upregulated in fibrotic kidneys after renal insults induced by folic acid administration. Compared with wild-type mice, PHF14-null mice showed more severe renal fibrosis after pro-fibrotic stimuli. Moreover, PHF14 in rat renal fibroblasts was upregulated by transforming growth factor-β (TGF-β) stimulation; while this upregulation was inhibited when smad3 phosphorylation was blocked. A chromatin immunoprecipitation (ChIP) assay further indicated that phospho-smad3 (p-smad3) acted as a transcription factor to enhance PHF14 expression. A lack of PHF14 expression enhanced collagen I and α-smooth muscle actin (α-SMA) synthesis induced by TGF-β in vitro. PHF14 was involved in inhibition of platelet-derived growth factor (PDGF) signaling overactivation by selectively repressing PDGF receptor-α (PDGFR-α) transcription. In summary, PHF14 expression was upregulated in fibrotic models in vivo and in vitro, and the TGF-β/smad3/PHF14 pathway acted as a self-limiting mechanism in the TGF-β-dominated renal pro-fibrotic process by suppressing PDGFR-α expression.
Highlights
PHF14 might play a role in renal tissue repair and regeneration during the progression of fibrosis after pro-fibrotic insults
PHF14 is upregulated in a folic acid-induced kidney fibrosis mouse model
Masson and immunohistochemical stainings of collagen I and α-smooth muscle actin (α-SMA) in kidney sections on day 14 and day 28 after folic acid injection confirmed the successful production of the folic acid-induced kidney fibrosis model (Fig. 1A)
Summary
PHF14 might play a role in renal tissue repair and regeneration during the progression of fibrosis after pro-fibrotic insults. Understanding the function of PHF14 will help to elucidate the interactions of mediators in the process of renal fibrogenesis. The primary objectives of this study were to investigate the expression profile of PHF14 in the scenario of TIF following acute kidney injury induced by folic acid, to illuminate the role of PHF14 in renal TIF, and to examine the interaction between PHF14 and TGF-βsignaling
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