| Autor: |
Rapahel Kopan, Naomi Podd-Shakked, Megan Slack, Nambirajan Sundaram, Ruth Schreiber, Benjamin Dekel, Michael Helmrath |
| Rok vydání: |
2023 |
| DOI: |
10.21203/rs.3.rs-2818846/v1 |
| Popis: |
Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder affecting proximal tubule (PT) development in patients harboring mutations in genes comprising the Renin–Angiotensin–Aldosterone System (RAAS). To uncover the pathomechanism of AR-RTD, we differentiated ACE and AGTR1 deficient pluripotent stem cells and reprogrammed AR-RTD patient cells into kidney organoids. Marker analyses confirmed that all mutant and control organoids generated PT in room air (21% O2) or under hypoxic conditions (2% O2). Mature (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engrafted and differentiated well, as did renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids failed to engraft due to insufficient pro-angiogenic VEGF-A expression. When grown under hypoxic conditions VEGF-A expression was stimulated and organoids engrafted. Thus, PT dysgenesis in AR-RTD is a non-autonomous consequence of a developmental delay in VEGF-A induction linking ANGII pro angiogenic role to PT dysgenesis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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