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

Ehtesham Arif, Ashish K. Solanki, Pankaj Srivastava, Bushra Rahman, Brian R. Tash, Lawrence B. Holzman, Michael G. Janech, René Martin, Hans Joachim Knölker, Wayne R. Fitzgibbon, Peifeng Deng, Milos N. Budisavljevic, Wing Kin Syn, Cindy Wang, Joshua H. Lipschutz, Sang Ho Kwon, Deepak Nihalani

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)139-158
Number of pages20
JournalKidney International
Volume96
Issue number1
DOIs
StatePublished - Jul 2019

Keywords

  • TGF-beta
  • fibrosis
  • focal segmental glomerulosclerosis
  • glomerulonephritis
  • glomerulus
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Arif, E., Solanki, A. K., Srivastava, P., Rahman, B., Tash, B. R., Holzman, L. B., Janech, M. G., Martin, R., Knölker, H. J., Fitzgibbon, W. R., Deng, P., Budisavljevic, M. N., Syn, W. K., Wang, C., Lipschutz, J. H., Kwon, S. H., & Nihalani, D. (2019). The motor protein Myo1c regulates transforming growth factor-β–signaling and fibrosis in podocytes. Kidney International, 96(1), 139-158. https://doi.org/10.1016/j.kint.2019.02.014