Angiotensin II biphasically regulates cell differentiation in human iPSC-derived kidney organoids

Area of Science:

• Stem cell biology and regenerative medicine
• Renal physiology and pathophysiology
• Developmental biology

Background:

• Human kidney organoids are promising models for studying kidney development and disease.
• The intrarenal renin-angiotensin system (RAS) and angiotensin II (ANG II) are critical in kidney development and injury.
• Understanding ANG II's role in kidney organoid differentiation is crucial for their application.

Purpose of the Study:

• To investigate the expression of RAS components in human kidney organoids.
• To determine the effects of ANG II on cell differentiation during organoid development.
• To elucidate the distinct roles of ANG II type 1 receptor (AT1R) and type 2 receptor (AT2R) in mediating these effects.

Main Methods:

• Generation of human induced pluripotent stem cell-derived kidney organoids using a modified Takasato protocol.
• Gene expression analysis via digital PCR and immunostaining to confirm renal compartment formation and RAS component expression.
• Treatment of organoids with ANG II during early (days 0-5) and middle (days 5-10) developmental phases, with and without AT1R and AT2R antagonists.

Main Results:

• RAS components were expressed in developing kidney organoids.
• Early ANG II exposure (ANG II-E) with AT1R activation decreased renal tubule markers, while middle phase exposure (ANG II-M) with AT2R activation increased podocyte and ureteric tip markers.
• Specific receptor antagonists (AT1R and AT2R blockers) modulated the respective ANG II-induced differentiation effects.

Conclusions:

• Human kidney organoids express RAS components and respond to ANG II in a biphasic manner.
• AT1R mediates inhibitory effects on renal tubule differentiation in early development.
• AT2R promotes differentiation of podocytes and other cell types in later developmental stages, offering novel strategies for organoid development and characterization.