The motor protein Myo1c regulates transforming growth factor-β-signaling and fibrosis in podocytes

Kidney Int. 2019 Jul;96(1):139-158. doi: 10.1016/j.kint.2019.02.014. Epub 2019 Mar 4.


Transforming growth factor-β (TGF-β) is known to play a critical role in the pathogenesis of many progressive podocyte diseases. However, the molecular mechanisms regulating TGF-β signaling in podocytes remain unclear. Using a podocyte-specific myosin (Myo)1c knockout, we demonstrate whether Myo1c is critical for TGF-β-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-β-dependent unilateral ureteral obstruction mouse model of renal interstitial fibrosis. Mechanistic analyses showed that loss of Myo1c significantly blunted TGF-β signaling through downregulation of canonical and non-canonical TGF-β pathways. Interestingly, nuclear rather than the cytoplasmic Myo1c was found to play a central role in controlling TGF-β signaling through transcriptional regulation. Differential expression analysis of nuclear Myo1c-associated gene promoters showed that nuclear Myo1c targeted the TGF-β 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-β-responsive genes is central to the pathogenesis of podocyte injury. Hence, inhibiting this process may have clinical application in treating podocytopathies.

Keywords: TGF-beta; fibrosis; focal segmental glomerulosclerosis; glomerulonephritis; glomerulus; podocyte.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Doxorubicin / toxicity
  • Female
  • Fibrosis
  • Gene Expression Regulation
  • Growth Differentiation Factor 15 / genetics*
  • Humans
  • Kidney Diseases / chemically induced
  • Kidney Diseases / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Myosin Type I / genetics
  • Myosin Type I / metabolism*
  • Podocytes / drug effects
  • Podocytes / pathology*
  • Promoter Regions, Genetic
  • Signal Transduction / genetics*
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism*


  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Myo1c protein, mouse
  • Transforming Growth Factor beta
  • Doxorubicin
  • Myosin Type I