| First Author | Arif E | Year | 2019 |
| Journal | Kidney Int | Volume | 96 |
| Issue | 1 | Pages | 139-158 |
| PubMed ID | 31097328 | Mgi Jnum | J:280249 |
| Mgi Id | MGI:6359085 | Doi | 10.1016/j.kint.2019.02.014 |
| Citation | Arif E, et al. (2019) The motor protein Myo1c regulates transforming growth factor-beta-signaling and fibrosis in podocytes. Kidney Int 96(1):139-158 |
| abstractText | Transforming growth factor-beta (TGF-beta) is known to play a critical role in the pathogenesis of many progressive podocyte diseases. However, the molecular mechanisms regulating TGF-beta signaling in podocytes remain unclear. Using a podocyte-specific myosin (Myo)1c knockout, we demonstrate whether Myo1c is critical for TGF-beta-signaling in podocyte disease pathogenesis. Specifically, podocyte-specific Myo1c knockout mice were resistant to fibrotic injury induced by Adriamycin or nephrotoxic serum. Further, loss of Myo1c also protected from injury in the TGF-beta-dependent unilateral ureteral obstruction mouse model of renal interstitial fibrosis. Mechanistic analyses showed that loss of Myo1c significantly blunted TGF-beta signaling through downregulation of canonical and non-canonical TGF-beta pathways. Interestingly, nuclear rather than the cytoplasmic Myo1c was found to play a central role in controlling TGF-beta signaling through transcriptional regulation. Differential expression analysis of nuclear Myo1c-associated gene promoters showed that nuclear Myo1c targeted the TGF-beta responsive gene growth differentiation factor (GDF)-15 and directly bound to the GDF-15 promoter. Importantly, GDF15 was found to be involved in podocyte pathogenesis, where GDF15 was upregulated in glomeruli of patients with focal segmental glomerulosclerosis. Thus, Myo1c-mediated regulation of TGF-beta-responsive genes is central to the pathogenesis of podocyte injury. Hence, inhibiting this process may have clinical application in treating podocytopathies. |
