Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0353-z
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Funding
- National Natural Science Foundation of China [81400732, 81370834, 30971381]
- Shandong Young Scientists Award Fund [2010BSB14076]
- Chinese Society of Nephrology Scientific Fund [14050480585]
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Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/beta-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes. In vitro, we showed Rac1/PAK1 physically bound to beta-catenin and had a direct phosphorylation modification on its C-terminal Ser675, leading to less ubiquitylated beta-catenin, namely more stabilized beta-catenin, and its nuclear migration under high-glucose conditions; further, p38 activation might be responsible for beta-catenin nuclear accumulation via potentiating myocyte-specific enhancer factor 2C (MEF2c) phosphorylation. These findings provided evidence for a potential renoprotective and therapeutic strategy of cell-specific Rac1 deficiency for DN and other proteinuric diseases.
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