First Author | Pace JA | Year | 2021 |
Journal | Sci Adv | Volume | 7 |
Issue | 36 | Pages | eabg6600 |
PubMed ID | 34516901 | Mgi Jnum | J:314198 |
Mgi Id | MGI:6766266 | Doi | 10.1126/sciadv.abg6600 |
Citation | Pace JA, et al. (2021) Podocyte-specific KLF4 is required to maintain parietal epithelial cell quiescence in the kidney. Sci Adv 7(36):eabg6600 |
abstractText | Podocyte loss triggering aberrant activation and proliferation of parietal epithelial cells (PECs) is a central pathogenic event in proliferative glomerulopathies. Podocyte-specific KrÃŒppel-like factor 4 (KLF4), a zinc-finger transcription factor, is essential for maintaining podocyte homeostasis and PEC quiescence. Using mice with podocyte-specific knockdown of Klf4, we conducted glomerular RNA-sequencing, tandem mass spectrometry, and single-nucleus RNA-sequencing to identify cell-specific transcriptional changes that trigger PEC activation due to podocyte loss. Integration with in silico chromatin immunoprecipitation identified key ligand-receptor interactions, such as fibronectin 1 (FN1)âαVβ6, between podocytes and PECs dependent on KLF4 and downstream signal transducer and activator of transcription 3 (STAT3) signaling. Knockdown of Itgb6 in PECs attenuated PEC activation. Additionally, podocyte-specific induction of human KLF4 or pharmacological inhibition of downstream STAT3 activation reduced FN1 and integrin β 6 (ITGB6) expression and mitigated podocyte loss and PEC activation in mice. Targeting podocyte-PEC crosstalk might be a critical therapeutic strategy in proliferative glomerulopathies. |