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

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

Author information

1
Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA.
2
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA; College of Charleston, Charleston, South Carolina, USA.
4
Department of Chemistry, TU Dresden, Dresden, Germany.
5
Department of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA; Section of Gastroenterology, Ralph H Johnson VA Medical Center, Charleston, South Carolina, USA; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, (UPV/EHU), Vizcaya, Spain.
6
Department of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA.
7
Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, USA.
8
Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address: nihalani@musc.edu.

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.

KEYWORDS:

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

PMID:
31097328
PMCID:
PMC6589397
[Available on 2020-07-01]
DOI:
10.1016/j.kint.2019.02.014

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