MassIVE MSV000093243

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Cytoskeleton-associated protein 4 (CKAP4) affects podocyte cytoskeleton dynamics in diabetic kidney disease

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Description

Cytoskeleton-associated protein 4 (CKAP4) stabilizes the endoplasmic reticulum, by regulating its folding and anchoring to the microtubular cytoskeleton. Since podocytes are highly dependent on an intact cytoskeleton to exert their function, the role of CKAP4 was explored during normal conditions and in diabetic kidney disease (DKD). Methods. The differences in CKAP4 gene expression between patients with chronic kidney disease (CKD) and controls were explored in publicly available databases. Expression of CKAP4 in patients with DKD was investigated with in situ hybridization. Localization in human kidney tissue was determined using immunofluorescence, qPCR, and western blot. The CKAP4 homolog was knocked down (KD) in zebrafish. Proteinuria and glomerular morphology were investigated. CKAP4 KD and overexpression in podocytes were investigated using proteomics, immunofluorescence, and western blot. Results. Glomerular CKAP4 gene expression was reduced in DKD patients compared to healthy individuals, but not in other CKDs. The glomerular expression of CKAP4 was most pronounced in podocytes. CKAP4 KD zebrafish became proteinuric and podocyte FPE (foot process effacement) was observed. CKAP4 KD in podocytes in vitro led to disruption of actin stress fibers, microtubular rearrangement and loss of integrin expression. Conclusion. CKAP4 reduction causes podocyte FPE and proteinuria in vivo. Loss of CKAP4 disrupts the podocyte actin cytoskeleton, its microtubular orientation, and integrin-based glomerular basement membrane attachment. This indicates that CKAP4 is a crucial connector between cell body and structural elements in podocytes. The reduction of CKAP4 observed in glomeruli from DKD patients may thus be coupled to impaired podocyte function and proteinuria. [doi:10.25345/C56H4D17V] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CKAP4 ; podocytes ; cytoskeleton ; diabetic kidney disease ; microtubules ; integrins

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Principal Investigators:
(in alphabetical order) 		Roberto Boi, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg,, Sweden
Submitting User: haiyanzheng
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