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 - Funding Information:
This work was supported in whole or in part by the NIH and NIDDK Grants 2R01DK087956-06A1 and R56 DK116887-01A1 to DN, the American Society of Nephrology Carl Gottschalk award to S-HK, the Ben J. Lipps Research Fellowship from the American Society of Nephrology to AKS, the Cell & Molecular Imaging Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313). We thank Babita Kumari for technical assistance in the laboratory. EA, AKS, PS, BR, TBR, WRF, PF, CW, and DN conducted the experiments and analyzed data. EA and DN generated the mouse strains. LBH, MGJ, RM, HJK, JHL, and WKS provided critical reagents and helped with experimental designs. SHK performed RNASeq analysis and interpretation. MNB provided human kidney biopsy samples. EA and DN designed the experiments, interpreted data, and wrote the article. All authors discussed results and commented on the article.
Funding Information:
This work was supported in whole or in part by the NIH and NIDDK Grants 2R01DK087956-06A1 and R56 DK116887-01A1 to DN, the American Society of Nephrology Carl Gottschalk award to S-HK, the Ben J. Lipps Research Fellowship from the American Society of Nephrology to AKS, the Cell & Molecular Imaging Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313). We thank Babita Kumari for technical assistance in the laboratory.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85065531881&partnerID=8YFLogxK
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 -