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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.
Abstract:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major renal pathology provoked by the deletion of PKD1 or PKD2 genes leading to local renal tubule dilation followed by the formation of numerous cysts, ending up with renal failure in adulthood. In vivo, renal tubules are tightly packed, so that dilating tubules and expanding cysts may have mechanical influence on adjacent tubules. To decipher the role of this coupling between adjacent tubules, we developed a kidney-on-chip reproducing parallel networks of tightly packed tubes. This original microdevice is composed of cylindrical hollow tubes of physiological dimensions, parallel and closely packed with 100-200 μm spacing, embedded in a collagen I matrix. These multitubular systems were properly colonized by different types of renal cells with long-term survival, up to 2 months. While no significant tube dilation over time was observed with Madin-Darby Canine Kidney (MDCK) cells, wild-type mouse proximal tubule (PCT) cells, or with PCT Pkd1 +/- cells (with only one functional Pkd1 allele), we observed a typical 1.5-fold increase in tube diameter with isogenic PCT Pkd1 -/- cells, an ADPKD cellular model. This tube dilation was associated with an increased cell proliferation, as well as a decrease in F-actin stress fibers density along the tube axis. With this kidney-on-chip model, we also observed that for larger tube spacing, PCT Pkd1 -/- tube deformations were not spatially correlated with adjacent tubes whereas for shorter spacing, tube deformations were increased between adjacent tubes. Our device reveals the interplay between tightly packed renal tubes, constituting a pioneering tool well-adapted to further study kidney pathophysiology.
Insights
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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