Transient (Pro)renin receptor silencing disrupts proximal tubule development in human kidney organoids

Abstract

The (pro)renin receptor [(P)RR] plays a crucial role in murine kidney development, but its function in human kidneys remains poorly understood due to the lack of suitable research models. Human induced pluripotent stem cell (iPSC)-derived kidney organoids recapitulate early kidney development and are therefore suitable to investigate the effects of (P)RR knockdown on nephron formation in a human setting. Human iPSC were differentiated into kidney organoids, and (P)RR was silenced using small interfering RNA delivered by nucleofection either at the primitive streak stage or during nephron progenitor cell induction. Organoid development was evaluated morphologically and by analysis of nephron markers at the mRNA and protein levels. We found that transient silencing of (P)RR during primitive streak formation resulted in smaller organoids, impaired proximal tubule formation, increased stromal cell populations, and promoted fibrosis, while podocyte and distal tubule development remained unaffected. In contrast, transient (P)RR knockdown during nephron progenitor cell induction selectively disrupted proximal tubule formation without affecting organoid size or the development of podocytes and distal tubules. Our findings demonstrate a pivotal role for (P)RR in human kidney development. This contributes to our understanding of kidney development disorders and identifies (P)RR as a potential target for future genetic and therapeutic interventions in renal hypoplasia and hypodysplasia.