SETD2 deficiency resulted in severe renal fibrosis in the absence of VHL, and based on these results, we found that SETD2 deletion can lead to reduced expression of Smad7 by H3K36me3, which activates the TGF‐β/Smad signalling pathway and leads to renal fibrosis. This evidence concerns the gene SETD2 and renal fibrosis.