PUBLICATION
Dissection of Glomerular Transcriptional Profile in Patients with Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function
- Authors
- Pan, Y., Jiang, S., Hou, Q., Qiu, D., Shi, J., Wang, L., Chen, Z., Zhang, M., Duan, A., Qin, W., Zen, K., Liu, Z.
- ID
- ZDB-PUB-171216-3
- Date
- 2017
- Source
- Diabetes 67(4): 717-730 (Journal)
- Registered Authors
- Chen, Zhaohong, Hou, Qing, Liu, Zhihong, Wang, Ling
- Keywords
- none
- MeSH Terms
-
- Adult
- Animals
- Carrier Proteins/genetics*
- Carrier Proteins/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/metabolism*
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/genetics*
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/pathology
- Disease Models, Animal
- Female
- GTPase-Activating Proteins/genetics*
- GTPase-Activating Proteins/metabolism
- Gene Expression Profiling
- Humans
- Kidney Glomerulus/metabolism*
- Male
- Mice
- Middle Aged
- Podocytes/ultrastructure*
- Zebrafish
- Zebrafish Proteins
- cdc42 GTP-Binding Protein/metabolism
- rac1 GTP-Binding Protein/metabolism
- rhoA GTP-Binding Protein/metabolism
- PubMed
- 29242313 Full text @ Diabetes
Citation
Pan, Y., Jiang, S., Hou, Q., Qiu, D., Shi, J., Wang, L., Chen, Z., Zhang, M., Duan, A., Qin, W., Zen, K., Liu, Z. (2017) Dissection of Glomerular Transcriptional Profile in Patients with Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function. Diabetes. 67(4):717-730.
Abstract
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 ρGTPase-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-β or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocyte motility 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping