TY - JOUR
T1 - The motor protein Myo1c regulates transforming growth factor-β–signaling and fibrosis in podocytes
AU - Arif, Ehtesham
AU - Solanki, Ashish K.
AU - Srivastava, Pankaj
AU - Rahman, Bushra
AU - Tash, Brian R.
AU - Holzman, Lawrence B.
AU - Janech, Michael G.
AU - Martin, René
AU - Knölker, Hans Joachim
AU - Fitzgibbon, Wayne R.
AU - Deng, Peifeng
AU - Budisavljevic, Milos N.
AU - Syn, Wing Kin
AU - Wang, Cindy
AU - Lipschutz, Joshua H.
AU - Kwon, Sang Ho
AU - Nihalani, Deepak
N1 - Publisher Copyright:
© 2019 International Society of Nephrology
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - TGF-beta
KW - fibrosis
KW - focal segmental glomerulosclerosis
KW - glomerulonephritis
KW - glomerulus
KW - podocyte
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U2 - 10.1016/j.kint.2019.02.014
DO - 10.1016/j.kint.2019.02.014
M3 - Article
C2 - 31097328
AN - SCOPUS:85065531881
SN - 0085-2538
VL - 96
SP - 139
EP - 158
JO - Kidney International
JF - Kidney International
IS - 1
ER -