RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis
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Read the article on pubmed.ncbi.nlm.nih.gov ↗Article · Dec 2023 · 1 min read
In brief
In brief
This study uses kidney organoids derived from patient iPSCs to reveal that autosomal recessive renal tubular dysgenesis results from delayed angiogenesis rather than intrinsic tubular defects. Researchers demonstrate that insufficient VEGF-A expression in RAAS-deficient organoids prevents engraftment, but hypoxic conditions or ectopic VEGF-A rescue proximal tubule development, suggesting vascular insufficiency as the primary pathomechanism.
Written by the GCMD Library team from the article.
Statements in this article
Autosomal recessive renal tubular dysgenesis is a fatal genetic disorder characterized by complete absence or severe depletion of proximal tubules in patients with pathogenic variants in genes involved in the renin-angiotensin-aldosterone system.
ACE-/- and AGTR1-/- mutant organoids and control organoids generate indistinguishable proximal tubules in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions.
Fully differentiated day 24 AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engraft and mature well.
Renal vesicle stage day 14 control organoids engraft well when transplanted under the kidney capsule.
Day 14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression.
Growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at day 14.
Ectopic expression of VEGF-A rescues engraftment of day 14 AGTR1-/- organoids.
Proximal tubule dysgenesis in autosomal recessive renal tubular dysgenesis is primarily a non-autonomous consequence of delayed angiogenesis that starves proximal tubules at a critical time in their development.