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RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis

Author

Listed:
  • Naomi Pode-Shakked

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Tel Aviv University)

  • Megan Slack

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Nambirajan Sundaram

    (Cincinnati Children’s Hospital Medical Center)

  • Ruth Schreiber

    (Soroka University Medical Center, Ben Gurion University of the Negev)

  • Kyle W. McCracken

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Benjamin Dekel

    (Tel Aviv University
    Edmond and Lily Safra Children’s Hospital, Sheba Medical Center)

  • Michael Helmrath

    (Cincinnati Children’s Hospital Medical Center)

  • Raphael Kopan

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

Abstract

Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder characterized by complete absence or severe depletion of proximal tubules (PT) in patients harboring pathogenic variants in genes involved in the Renin–Angiotensin–Aldosterone System. To uncover the pathomechanism of AR-RTD, differentiation of ACE-/- and AGTR1-/- induced pluripotent stem cells (iPSCs) and AR-RTD patient-derived iPSCs into kidney organoids is leveraged. Comprehensive marker analyses show that both mutant and control organoids generate indistinguishable PT in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions. Fully differentiated (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engraft and mature well, as do renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression. Notably, growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A. We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous consequence of delayed angiogenesis, starving PT at a critical time in their development.

Suggested Citation

  • Naomi Pode-Shakked & Megan Slack & Nambirajan Sundaram & Ruth Schreiber & Kyle W. McCracken & Benjamin Dekel & Michael Helmrath & Raphael Kopan, 2023. "RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43795-x
    DOI: 10.1038/s41467-023-43795-x
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