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Abstract: PO0669

The Role of Cytoskeleton-Associated Protein 4 in the Glomerulus and Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Johansson, Alva, Goteborgs universitet Institutionen for neurovetenskap och fysiologi, Goteborg, Sweden
  • Lassen, Emelie, Goteborgs universitet Institutionen for neurovetenskap och fysiologi, Goteborg, Sweden
  • Müller-Deile, Janina, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Boi, Roberto, Goteborgs universitet Institutionen for neurovetenskap och fysiologi, Goteborg, Sweden
  • Schiffer, Mario, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany
  • Nystrom, Jenny C., Goteborgs universitet Institutionen for neurovetenskap och fysiologi, Goteborg, Sweden
  • Ebefors, Kerstin, Goteborgs universitet Institutionen for neurovetenskap och fysiologi, Goteborg, Sweden
Background

Cytoskeleton-associated protein 4 (CKAP4) was first discovered in the endoplasmic reticulum (ER) where it links the ER to the cytoskeleton. It can also be located in the cell membrane and function as a receptor. CKAP4 has been shown to be involved in various physiological events besides its function in the ER, including cell proliferation and migration. In this study, we explored the function of CKAP4 in the glomerulus and its role in chronic kidney disease (CKD).

Methods

Glomerular CKAP4 gene expression was evaluated in different CKD cohorts. The expression of CKAP4 in human glomeruli was investigated via immunofluorescence and western blot. The CKAP4 homolog in zebra fish was knocked down (KD) in vivo and proteinuria and morphology were analyzed. shRNA was used to KD CKAP4 in human podocyte and mesangial cells in vitro. Changes in protein expression was analyzed via mass spectrometry and western blot, and the morphology of the actin cytoskeleton via immunofluorescence.

Results

Analysis of different human CKD cohort revealed that CKAP4 was down regulated in glomeruli from patients with diabetic kidney disease (DKD), but not in the other diseases investigated. CKAP4 was expressed by all glomerular cells, but to lesser extent in endothelial cells. KD of the zebra fish CKAP4 homolog rendered the fish proteinuric and led to podocyte effacement. KD of CKAP4 in human podocytes and mesangial cells led to loss of actin stress fibers in both cell types. In addition, the expression of several growth factor receptors was affected, with a prominent loss of PDGF receptors in the mesangial cells reducing their proliferative response to PDGF.

Conclusion

Our results from the in vivo and in vitro experiments show that reduced expression of CKAP4 leads to glomerular dysfunction and changes in the actin cytoskeleton. In podocytes, this is known to cause foot process effacement which we observed. Less is known about how dysregulation of the actin cytoskeleton affects the mesangial cells, but we found that mesangial cells with CKAP4 KD downregulated their PDGF receptors, and had a reduced proliferative capacity. As patients with DKD have a low expression of CKAP4, we suggest that CKAP4 regulation can be a part of the disease development and progression.

Funding

  • Private Foundation Support