Abstract: TH-PO1113
Purinergic Calcium Signaling Drives Tubulointerstitial Cross-Talk in Kidney Diseases
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Figurek, Andreja, Insitute of Anatomy, University of Zurich, Zurich, Switzerland
- Jankovic, Nevena, Insitute of Anatomy, University of Zurich, Zurich, Switzerland
- Kollar, Sarah, Insitute of Anatomy, University of Zurich, Zurich, Switzerland
- Hall, Andrew, Insitute of Anatomy, University of Zurich, Zurich, Switzerland
Background
Chronic kidney disease (CKD) is a major global health problem with limited treatment options. In response to injury proximal tubules (PTs) release factors that activate surrounding fibroblasts to a pro-fibrotic phenotype, which then drives progressive organ damage. Identifying signaling mechanisms between PTs and fibroblasts could reveal new targets for therapeutic intervention. Calcium is a vital intracellular second messenger that regulates many processes, but the nature of calcium signaling in renal fibroblasts was previously not well understood.
Methods
Multiphoton imaging of the kidney ex vivo and in vivo in transgenic mice expressing a calcium reporter in renal fibroblasts; confocal imaging of calcium activity in normal rat kidney fibroblasts in vitro; histological analysis in fixed tissue.
Results
Interstitial fibroblasts in the kidney display spontaneous calcium transients that originate in processes before spreading across the cell, and which markedly increase in frequency in models of acute tubular injury (cisplatin toxicity) and CKD/renal fibrosis (unilateral ureteric obstruction – UUO). Exposing fibroblasts to UDP or synthetic agonists of its target receptor P2Y6 produced acute rises in intracellular calcium. P2Y6R activation also stimulated fibroblast proliferation and migration, and expression of pro-fibrotic markers in vitro. In mice exposed to UUO, affected kidneys showed P2Y6R transcriptional up-regulation and knock out or pharmacological inhibition of the P2Y6R decreased fibroblast proliferation, myofibroblast activation, macrophage proliferation, and collagen 1 expression. Moreover, blocking the P2Y6R decreased fibroblast and macrophage proliferation, and myofibroblast activation in another well-established model of CKD (folic acid nephropathy).
Conclusion
We provide evidence that purinergic mediated calcium signaling mediates tubulo-interstitial cross-talk in CKD and that the P2Y6R could represent a therapeutic target.