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

被引：20

作者：

Arif, Ehtesham ^{[1
]}

Solanki, Ashish K. ^{[1
]}

Srivastava, Pankaj ^{[1
]}

Rahman, Bushra ^{[1
]}

Tash, Brian R. ^{[2
]}

Holzman, Lawrence B. ^{[2
]}

Janech, Michael G. ^{[1
,3
]}

Martin, Rene ^{[4
]}

Knolker, Hans-Joachim ^{[4
]}

Fitzgibbon, Wayne R. ^{[1
]}

Deng, Peifeng ^{[1
]}

Budisavljevic, Milos N. ^{[1
]}

Syn, Wing-Kin ^{[5
,6
,7
]}

Wang, Cindy ^{[5
]}

Lipschutz, Joshua H. ^{[1
]}

Kwon, Sang-Ho ^{[8
]}

Nihalani, Deepak ^{[1
]}

机构：

[1] Med Univ South Carolina, Dept Med, Nephrol Div, Charleston, SC 29425 USA

[2] Univ Penn, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[3] Coll Charleston, Charleston, SC 29401 USA

[4] Tech Univ Dresden, Dept Chem, Dresden, Germany

[5] Med Univ South Carolina, Dept Gastroenterol & Hepatol, Charleston, SC 29425 USA

[6] Ralph H Johnson VA Med Ctr, Sect Gastroenterol, Charleston, SC USA

[7] Univ Basque Country, UPV EHU, Fac Med & Nursing, Dept Physiol, Vizcaya, Spain

[8] Augusta Univ, Dept Cellular Biol & Anat, Augusta, GA USA

来源：

KIDNEY INTERNATIONAL | 2019年 / 96卷 / 01期

关键词：

fibrosis; focal segmental glomerulosclerosis; glomerulonephritis; glomerulus; podocyte; TGF-beta; TGF-BETA; RENAL FIBROSIS; MYOSIN-I; ADRIAMYCIN NEPHROPATHY; THERAPEUTIC TARGET; ACTIN; NEPHRIN; ACTIVATION; MECHANISMS; BINDING;

D O I：

10.1016/j.kint.2019.02.014

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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

引用

页码：139 / 158

页数：20

共 80 条

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