A kidney specific mouse model to study the effects of in vivo induction of Yamanaka factors

Lemberg, K.; Franken, G. A. C.; Riedhammer, K. M.; Holzel, S.; Yousef, K.; Lomjansook, K.; Kalkar, G.; Kolvenbach, C. M.; Marchuk, D.; Zion, E.; Saida, K.; Hildebrandt, F.

doi:10.1101/2025.08.30.672899

bioRxiv · 10.1101/2025.08.30.672899

A kidney specific mouse model to study the effects of in vivo induction of Yamanaka factors

Lemberg, K.·Franken, G. A. C.·Riedhammer, K. M.·Holzel, S.·Yousef, K.·Lomjansook, K.·Kalkar, G.·Kolvenbach, C. M.·Marchuk, D.·Zion, E.·Saida, K.·Hildebrandt, F.

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Abstract

IntroductionMaladaptive repair after acute kidney injury (AKI) leads to fibrosis and chronic kidney disease (CKD). Improving the resilience and stimulating tissue repair after injury is crucial to prevent AKI-to-CKD transition. Using a combination of transcription factors (Yamanaka factors Oct4, Klf4 and Sox2, "OKS") to partially reprogram tissues and enhance regeneration in vivo, could be a promising approach as shown by amelioration after various organ injury, yet not investigated for AKI to date. MethodsWe used a ubiquitously and kidney-specific transgenic mouse model to investigate OKS expression in kidney. In a kidney-specific model using Pax8-Cre, we then induced AKI via aristolochic acid (AA), simultaneously expressing OKS to determine potential protective effects after kidney injury. ResultsWe show that a ubiquitously expressing OKS-mouse model was not suitable due to toxic effects and limited kidney expression. In the Pax8-Cre mouse model, we observed expression almost exclusively to proximal tubules. While induction for more than 3 days caused dysplastic tumor formation, an induction regimen limited to 3 days was not able to improve phenotypic outcome after AA-injury. ConclusionPartial reprogramming of the kidney using OKS is feasible; however, it requires a delicate balance to the risk of oncogenic transformation. Determine a dose that effectively promotes repair without crossing the threshold into harmful effects remains a major challenge, posing significant safety concerns for translating the approach to humans in the near future.

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Lemberg, K., Franken, G. A. C., Riedhammer, K. M., Holzel, S., Yousef, K., Lomjansook, K., Kalkar, G., Kolvenbach, C. M., Marchuk, D., Zion, E., Saida, K., Hildebrandt, F.. 2025-09-04. A kidney specific mouse model to study the effects of in vivo induction of Yamanaka factors. https://doi.org/10.1101/2025.08.30.672899

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