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A Multitubular Kidney-on-Chip to Decipher Pathophysiological Mechanisms in Renal Cystic Diseases
Sarah Myram1, Bastien Venzac1, Brice Lapin1
1Institut Curie, Université PSL (Paris Sciences & Lettres), Sorbonne Université, CNRS UMR 168, Laboratoire Physico Chimie Curie, Paris, France.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) involves gene deletions causing kidney cysts. A new kidney-on-chip model shows that closely packed kidney tubules influence cyst development, revealing mechanical interplay in ADPKD progression.
Area of Science:
- Nephrology
- Biotechnology
- Cell Biology
Background:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by kidney tubule dilation and cyst formation, often leading to renal failure.
- The mechanical interactions between adjacent renal tubules in vivo are not fully understood, particularly in the context of ADPKD pathogenesis.
Purpose of the Study:
- To develop and utilize a novel kidney-on-chip model to investigate the mechanical coupling between parallel renal tubules in ADPKD.
- To elucidate the role of tubule proximity and Pkd1 gene deletion in ADPKD cystogenesis.
Main Methods:
- A microfluidic device was engineered to mimic parallel, closely packed renal tubules (100-200 μm spacing) embedded in a collagen I matrix.
- Renal cells, including wild-type and Pkd1-deficient mouse proximal tubule (PCT) cells, were cultured within the microdevice for up to 2 months.
- Tube diameter, cell proliferation, F-actin density, and spatial correlation of deformations between adjacent tubes were quantified.
Main Results:
- PCT cells lacking functional Pkd1 (Pkd1-/-) exhibited a 1.5-fold increase in tube diameter, indicative of cyst formation, compared to wild-type or Pkd1+/- cells.
- Tube dilation in Pkd1-/- cells was associated with increased cell proliferation and reduced F-actin stress fibers.
- Mechanical deformations of Pkd1-/- tubes were spatially correlated with adjacent tubes when spacing was reduced (100-200 μm), but not when spacing was larger.
Conclusions:
- The kidney-on-chip model successfully replicates key aspects of ADPKD, including tubule dilation and the influence of mechanical forces.
- Close packing of renal tubules exacerbates ADPKD-related deformations, highlighting the importance of mechanical interplay in disease progression.
- This microdevice serves as a valuable tool for studying kidney pathophysiology and exploring potential therapeutic targets for ADPKD.
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