Shear stress regulated signaling in renal epithelial cells and polycystic kidney disease

Kunnen, S.J. (2018)

Doctoral Thesis

Several cellular processes and pathways were altered both by fluid shear stress and Pkd1 gene disruption in renal epithelial cells. Many of these signaling pathways are implicated in ADPKD as well. However, more than 20 years after the discovery of PKD1 and PKD2 as genetic cause of ADPKD, the exact cellular function of the polycystins still remains unclear. Our data indicate that polycystin-1 is not a direct mechano-sensor, but it restrains shear stress induced gene expression via an unknown mechanism. Additional research is required to identify the cellular function of polycystins and the mechanism of mechanotransduction. This is needed to refine the mechanism of cyst formation in ADPKD and other ciliopathies, which could identify potential targets for therapy. Nevertheless, we showed that inhibition of activin signaling is a promising therapy to slow cyst progression in Pkd1del mice. Although other treatment strategies have been tested successfully to reduce PKD progression in pre-clinical studies, the efficacy in human patients is sometimes minimal or absent. Therefore, it has been suggested to target multiple signaling pathways affected in ADPKD. These combined therapies should reestablish the balance in cellular signaling of renal epithelial cells and maintain cellular homeostasis within physiological boundaries.

• Mechanotransduction
• Fluid flow
• Cilia
• Pkd1-/-
• ADPKD
• Renal disease
• Proximal tubular epithelial cell
• RNA sequencing
• TGF-β

• All authors: Kunnen, S.J.
• Supervisor: Peters, D.J.M.
• Committee: Dijke, P. ten; Bindels, R.J.M.; Roepman, R.; Bakker, A.D.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-09-27
• ISBN (print): 9789493014398
• Sponsorship: Nederlandse organisatie voor wetenschappelijk onderzoek