Journal
DIABETES
Volume 67, Issue 4, Pages 717-730Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0755
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Funding
- National Key Research and Development Program of China [2016YFC0904100]
- National Key Technology RD Program [2015BAI12B02]
- Major International (Regional) Joint Research Project [81320108007]
- Key Research and Development Program of Jiangsu Province [BE2016747]
- National Natural Science Foundation of China [81500548, 81500556, 81300652]
- Innovation Capability Development Project of Jiangsu Province [BM2015004]
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Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern the podocyte cytoskeletal rearrangement remain unclear. Through analyzing the transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO rGTPase-activating protein 2a (SRGAP2a) as one of the main hub genes strongly associated with proteinuria and glomerular filtration in type 2 DN. Immunofluorescence staining and Western blot analysis revealed that human and mouse SRGAP2a is primarily localized at podocytes and largely colocalized with synaptopodin. Moreover, podocyte SRGAP2a is downregulated in patients with DN and db/db mice at both the mRNA and the protein level. SRGAP2a reduction is observed in cultured podocytes treated with tumor growth factor-beta or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocytemotility through inactivating RhoA/Cdc42 but not Rac1. The protective role of SRGAP2a in podocyte function also is confirmed in zebrafish, in which knockdown of SRGAP2a, a SRGAP2 ortholog in zebrafish, recapitulates podocyte foot process effacement. Finally, increasing podocyte SRGAP2a levels in db/db mice through administration of adenovirus-expressing SRGAP2a significantly mitigates podocyte injury and proteinuria. The results demonstrate that SRGAP2a protects podocytes by suppressing podocyte migration.
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