Injury-induced FoxM1 expression in mouse kidney drives epithelial proliferation by a Cyclin F dependent mechanism

Acute kidney injury strongly upregulates the transcription factor Foxm1 in proximal tubule in vivo and Foxm1 drives epithelial proliferation in vitro. Here we report that deletion of Foxm1 either with a nephron specific Cre driver or by inducible global deletion reduces proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI-to-CKD transition with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report extracellular signal-regulated kinase (ERK) mediates FOXM1 induction downstream of the epidermal growth factor receptor (EGFR) in primary proximal tubule cells. We defined FOXM1 genomic binding sites by Cleavage Under Targets & Release Using Nuclease (CUT&RUN) and compared the genes located near FOXM1 binding sites with genes downregulated in primary proximal tubule cells after FOXM1 knockdown. The aligned datasets revealed the cell cycle regulator cyclin F (CCNF) as a putative FOXM1 target. We identify two cis regulatory elements that bind FOXM1 and regulate CCNF expression, demonstrate that Ccnf is strongly induced after kidney injury and that Foxm1 deletion abrogates Ccnf expression in vivo and in vitro. Knockdown of CCNF also reduced proximal tubule proliferation in vitro. These studies identify an ERK-FOXM1-CCNF signaling pathway that regulates injury-induced proximal tubule cell proliferation.

Cell biology; Cell cycle; Nephrology.