Calcium signalling controls podocyte morphogenesis
| Autor: | Iain A. Drummond, Heiko Schenk, Alejandro Hidalgo-Gonzalez, Irene M. Ghobrial, Jan Hegermann, Lynne Beverly-Staggs, Aude Dorison, Ritu Tomar, Lydia Djenoune, Melissa H. Little |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
SERCA 030232 urology & nephrology chemistry.chemical_element Calcium Podocyte Nephrin 03 medical and health sciences 0302 clinical medicine medicine Morphogenesis Humans Calcium Signaling Zebrafish Calcium signaling biology Podocytes General Medicine Inositol trisphosphate receptor biology.organism_classification Cell biology 030104 developmental biology medicine.anatomical_structure Basic Research chemistry Nephrology biology.protein Glomerular Filtration Barrier |
| Zdroj: | J Am Soc Nephrol |
| ISSN: | 1759-507X |
| Popis: | Background Podocytes are critical to maintaining the glomerular filtration barrier, and mutations in nephrotic syndrome genes are known to affect podocyte calcium signaling. However, the role of calcium signaling during podocyte development remains unknown. Methods We undertook live imaging of calcium signaling in developing podocytes, using zebrafish larvae and human kidney organoids. To evaluate calcium signaling during development and in response to channel blockers and genetic defects, the calcium biosensor GCaMP6s was expressed in zebrafish podocytes. We used electron microscopy to evaluate filtration barrier formation in zebrafish, and Fluo-4 to detect calcium signals in differentiating podocytes in human kidney organoids. Results Immature zebrafish podocytes (2.5 days postfertilization) generated calcium transients that correlated with interactions with forming glomerular capillaries. Calcium transients persisted until 4 days postfertilization, and were absent after glomerular barrier formation was complete. We detected similar calcium transients in maturing human organoid glomeruli, suggesting a conserved mechanism. In both models, inhibitors of SERCA or IP3 receptor calcium-release channels blocked calcium transients in podocytes, whereas lanthanum was ineffective, indicating the calcium source is from intracellular podocyte endoplasmic-reticulum stores. Calcium transients were not affected by blocking heartbeat or by blocking development of endothelium or endoderm, and they persisted in isolated glomeruli, suggesting podocyte-autonomous calcium release. Inhibition of expression of phospholipase C-γ1, but not nephrin or phospholipase C-e1, led to significantly decreased calcium activity. Finally, blocking calcium release affected glomerular shape and podocyte foot process formation, supporting the critical role of calcium signaling in glomerular morphogenesis. Conclusions These findings establish podocyte cell-autonomous calcium signaling as a prominent and evolutionarily conserved feature of podocyte differentiation and demonstrate its requirement for podocyte foot process formation. |
| Databáze: | OpenAIRE |
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