Figure 6: Summary Schematic-.

WT-Sh3 overexpressing mice mimic the Shroom3 excess in the kidneys of humans with the Shroom3 risk alleles which facilitates SHROOM3-ROCK1 and/or ROCK2 interaction in specific cell types in vivo. When kidney injury is induced (predominantly tubular injury) by either AAN or UUO the augmented ROCK1/2 activation within iPTs leads to increased TIF after injury attributable to increased Wnt/Ctnnb1 and TGFβ1 signals and downstream expression of pro-fibrotic markers, pro-inflammatory cytokines and chemokines (promoting fibro-inflammation). Together, these promote TIF. This is a mechanism that underlies faster progression to CKD in AKI patients with the Shroom3 risk alleles. Meanwhile, overexpressing ASD2Δ-Sh3 in the same cells in vivo abolishes ROCK1/2 interaction and reduces activation and reduced post-injury TIF in kidneys of ASD2Δ-Sh3 mice. Also, the data indicates a dominant negative effect of ASD2Δ-Sh3 overexpression over the endogenous Shroom3 activity. Our findings indicate the therapeutic potential of cell-specific inhibition of SHROOM3-ROCK1 and/or ROCK2 interaction for TIF and CKD progression in humans. (iPTs -injured proximal tubular cells) Created with BioRender.com