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

Naomi Pode-Shakked, Megan Slack, Nambirajan Sundaram, Ruth Schreiber, Kyle W. McCracken, Benjamin Dekel, Michael Helmrath and Raphael Kopan ()
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Naomi Pode-Shakked: University of Cincinnati College of Medicine
Megan Slack: University of Cincinnati College of Medicine
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
Benjamin Dekel: Tel Aviv University
Michael Helmrath: Cincinnati Children’s Hospital Medical Center
Raphael Kopan: University of Cincinnati College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43795-x

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