The (pro)renin receptor is involved in kidney organoid development

Objective: The (pro)renin receptor [(P)RR], a receptor for prorenin and renin, is widely distributed in the body, including the kidneys. Studies in (P)RR knockout mouse models indicate that (P)RR ablation can be detrimental to renal development and function. However, the lack of human models hinders investigation into the role of (P)RR in human kidney development. The advent of human induced pluripotent stem cell (iPSC) – derived kidney organoids provides a tool to study the role of (P)RR in human kidney development. Design and method: To investigate the effects of (P)RR knockdown on kidney organoid development, human iPSC – derived kidney organoids were generated according to a previously described protocol. We silenced the (P)RR by introducing (P)RR antisense oligonucleotides (ASOs) by electroporation at the stage of iPSCs and nephron progenitor cells induction, respectively. The development of kidney organoids was monitored morphologically and through protein expression analysis of nephron markers by immunohistochemistry staining which was quantified by Image J. Results: After silencing the (P)RR at the initial stage of differentiation, the size of iPSCs-derived organoids was substantially smaller, but the size of tubular structures was bigger. We observed a decrease by 50% in both WT1 (glomerular cell marker) and PDGFR↑ (stromal cell marker) expressions in (P)RR-knockdown organoids, a 4-fold and 2-fold increase in expressions of fibrogenic cell markers ↑-SMA and COL1A1 respectively, and no change in Villin1 (proximal tubular cell marker) and Cadherin-1 (distal tubular cell marker) expression. Additionally, (P)RR knockdown at the stage of nephron progenitor cells induction decreased the expressions of Villin1 and Cadherin-1 in organoids by 50% and 60% separately, while it induced a 4-, 3-, 2- and 2-fold increase in the expressions of CD31 (endothelial cell marker), PDGFR↑, ↑-SMA and COL1A1 respectively. Conclusions: This study shows that (P)RR silencing at the initial stage of differentiation or at the stage of nephron progenitor cells induction impaired normal development of kidney organoids. Its absence caused a shift into the direction of fibrogenic cells. This study provides new insights into the understanding the role of (P)RR in human kidney development.