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Human kidney organoid technology holds promise for novel kidney disease treatment strategies and utility in pharmacological and basic science. Given the crucial roles of the intrarenal renin-angiotensin system (RAS) and angiotensin II (Ang II) in the progression of kidney development and injury, we investigated expression of RAS components and effects of Ang II on cell differentiation in human kidney organoids. The human induced pluripotent stem cell (hiPSC)-derived kidney organoids were induced using a modified 18-day Takasato protocol. Gene expression analysis by digital PCR and immunostaining demonstrated formation of renal compartments and expression of RAS components. Ang II type 1 receptor (AT1R) was strongly expressed in the early phase of organoid development (around day 0), whereas Ang II type 2 receptor (AT2R) expression levels peaked on day 5. Thus, the organoids were treated with 100 nM Ang II in the early phase on day 0-5 (Ang II-E) or during the middle phase on day 5-10 (Ang II-M). Ang II-E was observed to decrease levels of marker genes for renal tubules and proximal tubules, and the downregulation of renal tubules was inhibited by an AT1R antagonist. In contrast, Ang II-M increased levels of markers for podocytes, ureteric tip, and nephrogenic mesenchyme, and an AT2R blocker attenuated the Ang II-M-induced augmentation of podocyte formation. The findings demonstrate RAS expression and Ang II exertion of biphasic effects on cell differentiation through distinct mediatory roles of AT1R and AT2R, providing a novel strategy to establish and further characterize the developmental potential of hiPSC-derived kidney organoids.
American Journal of Physiology-Renal Physiology – The American Physiological Society
Published: Nov 1, 2021
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