Podocyte Maturation in Human Kidney Organoids Is Accelerated With Renin-Angiotensin System Activation
Bibliographic record
Abstract
Background: The global prevalence of chronic kidney disease (CKD) is approximately 10% and rising. Current renal replacement modalities carry a significant socioeconomic burden and will struggle to meet rising demands. Pluripotent stem cellderived kidney organoids have emerged as a promising alternative for providing functional nephrons to CKD patients. This technology faces many challenges including maturation as they resemble first and second-trimester fetal kidneys. The renin-angiotensin system (RAS) is critical for normal kidney morphogenesis. Indeed, prenatal exposure to RAS inhibitors is associated with kidney dysgenesis and mortality. We hypothesize that Ang II and RAS inhibitors perturb developmental programs within nephron progenitor populations and alter cell fate specification and maturation of glomerular epithelial cells within kidney organoids. Methods: We performed single-cell RNA sequence analyses on human iPSC-derived kidney organoids treated acutely (24hrs) with vehicle, Ang II, losartan, or Ang II and losartan on 28th day of the Takasato protocol. Results: Kidney organoids expressed all major RAS genes (AGT, ACE1, ACE2, REN, AGTR1, and AGTR2) within expected cell populations. REN expression was downregulated by Ang II and normalized with losartan pre-treatment suggesting a functioning RAS network. We identified 3 late podocyte (LP) clusters, 1 early podocyte (EP) cluster, 1 parietal epithelial (PEC) cluster, and 2 nephron progenitor (NPC) clusters. The EP and NPC transcriptional profiles were disproportionately sensitive to Ang II as we noted significant upregulation of podocyte differentiation genes such as BMP7, FOXC2, PODXL, and NPHS2. Moreover, Ang II depleted the immature populations (NPC and EP) and expanded mature cell states (PEC and LP). Losartan downregulated podocyte differentiation programs and increased the proportion of immature cells (EP and NPC). Conclusions: Human kidney organoids developed a functioning intra-organoid RAS resembling in vivo intrarenal RAS. The lineage plasticity observed between NPCs, EPs, PECs, and LPs was sensitive to acute RAS perturbation. Ang II accelerated podocyte maturity while RAS inhibition held podocytes in an immature state. The next steps include testing different Ang II treatment durations, validating findings using immunocytochemistry, and reproducing this analysis on endothelial and tubule cells.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".