Kidney cancer is the 14th most common cancers in the world, among which clear cell renal cell carcinoma (ccRCC) is the most common subtype. VHL inactivation is the most common mutation seen in ccRCC with more than 90% of tumours had clonal disruption of the VHL pathway. Although it is the initial oncogenic insult in ccRCC, it takes decades after VHL inactivation for ccRCC to develop. To investigate the molecular mechanisms of ccRCC development, a mouse model with inducible inactivation of Vhl and Pbrm1 genes in kidney epithelial cells was used. single cell RNA sequencing (scRNA-seq) was performed to track the phenotypic evolution of Vhl / Pbrm1 null cells towards early carcinomas. The first transition was seen 10 months after Vhl / Pbrm1 inactivation with upregulation of stress- related transcription factors (TFs) including Fos, Junb, Egr1 and Atf3. Interestingly, these 4 TFs showed upregulation in normal proximal tubule (PT) cells as mice get older. The second wave showed upregulation of Sox4 and Sox9, which are involved in kidney epithelial cell regeneration. Single cell ATAC sequencing (scATAC-seq) experiment confirmed the functional importance of these TFs in early ccRCC cells. Although the expression of these TFs in normal kidney epithelial cells decrease after some time, they continued to be expressed at high level in ccRCC. Therefore, it seems that the initiation of ccRCC could be induced by unresolved response to the cell injury and tissue repair.