Single-cell RNA sequencing of kidney tissue from a conditional Vhlh knockout mouse model. [sc-RNA_Seq]

A well-established early oncogenic event in ccRCC tumorigenesis is the loss of the tumor suppressor gene von Hippel-Lindau (VHL), which occurs in roughly 80% of cases. However, deletion of Vhlh— the mouse VHL locus —alone is insufficient to drive malignant ccRCC development in mouse models.

Previously, we generated a conditional Vhlh knockout model targeting a subset of kidney epithelial cells using Hoxb7 promoter-driven Cre recombinase (Hoxb7-Cre-GFP; VhlhloxP/loxP, henceforth Vhlh-KO). This model recapitulates several features of premalignant ccRCC, including immune cell infiltration, fibrosis, epithelial hyperplasia in cortical and medullary tubules, pseudohypoxic responses (e.g., metabolic reprogramming and increased angiogenesis), and the presence of clear-cell clusters.