Key result
Fibroblast-specific deletion of Keap1 and consequent Nrf2 activation attenuated pathological fibrosis in mouse models of pressure overload heart failure and renal fibrosis.
Why the study?
Tissue fibrosis is common in heart failure and chronic kidney disease, but fundamental treatments remain lacking, motivating the search for novel antifibrotic mechanisms targeting fibroblast activation.
Does fibroblast-specific Keap1 deletion prevent pathological fibrosis and cardiac dysfunction in mouse models of pressure overload?
Does fibroblast-specific Keap1 deletion prevent pathological fibrosis and cardiac dysfunction in mouse models of pressure overload?
Fibroblast Nrf2 transcriptionally represses fibrosis-related genes, and fibroblast-specific deletion of Keap1 attenuates pathological fibrosis in pressure overload heart failure.
Animal data do not alter practice; hypothesis-generating for Nrf2-targeted antifibrotic strategies in human HF.
Background Tissue fibrosis is a common feature of many organ dysfunctions, such as heart failure and chronic kidney disease. However, no fundamental treatment has been developed. This study aims to identify novel molecular mechanisms for antifibrotic intervention, focusing on fibroblast activation. Methods We performed a forward genetic screen using a genome-wide CRISPR library in the context of transforming growth factor β (TGF-β)-mediated connective tissue growth factor (CTGF) expression, and used unbiased techniques such as Cleavage Under Targets and Tagmentation (CUT&Tag) and proximity-dependent biotin labeling by TurboID to reveal the detailed molecular mechanisms. Results CRISPR library screening identified a number of players in both the canonical Smad pathway and the non-canonical pathway. In addition to the known factors, the Keap1-Nrf2 pathway was identified as a predominant regulator of TGF-β-mediated CTGF expression. Keap1 deletion and consequent Nrf2 activation broadly suppressed profibrotic gene expression, independently of conventional antioxidant effects. CUT&Tag revealed that Nrf2 bound to the proximity of fibrosis-related genes including Ctgf and Fn1. Subsequent individual analysis revealed Smad3 and RNA polymerase II binding to the Nrf2 peak site, which was attenuated by Keap1 deletion. TurboID experiments further discovered that Nrf2 interacts with Ddx54, which acts as a corepressor. Consistently, Keap1 deletion-mediated repression of profibrotic gene expression was reversed by additional Ddx54 deletion. The impact of the Keap1-Nrf2 pathway on pathological fibrosis was examined using tamoxifen-inducible fibroblast-specific Keap1 knockout mice. Pressure overload for 4 weeks robustly induced cardiac hypertrophy, fibrosis and contractile dysfunction. However, deletion of Keap1 in the Postn lineage attenuated these cardiac pathologies. The anti-fibrotic effects of Keap1 deletion were also confirmed in renal fibrosis in the unilateral ureteral obstruction (UUO) model. Conclusions Fibroblast Nrf2 transcriptionally represses fibrosis-related genes in cooperation with the corepressor Ddx54. Fibroblast-specific deletion of Keap1 attenuated pathological fibrosis in pressure overload heart failure and renal fibrosis.
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Nishiji et al. (2023) studied Tissue fibrosis (heart failure and chronic kidney disease). Keap1 deletion / Nrf2 activation vs. Control was evaluated on Pathological fibrosis and profibrotic gene expression. Fibroblast-specific deletion of Keap1 and consequent Nrf2 activation attenuated pathological fibrosis in mouse models of pressure overload heart failure and renal fibrosis.
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