Fig. 9: Summary figure showing efficacy of a P2I (D4G) to target this protein-protein interaction.
From: Design of precision therapeutics for a CKD risk allele by targeting Shroom3-Rock interaction
WT-Sh3 overexpressing mice were generated to mimic Shroom3 excess in the kidney cells of humans with CKD-associated, enhancer, Shroom3 SNPs. During injury (AAN or UUO), excess SHROOM3 facilitates interaction with Rho-kinases in iPTs. In this milieu, augmented ROCK1, −2 activation within iPTs leads to increased TIF after injury via increased Wnt/Ctnnb1- and Tgfβ1- pro-fibrotic signals as well as pro-inflammatory signals, promoting “fibro-inflammation”, progressive TIF after injury and CKD. This likely explains the mechanism underlying the risk of CKD with Shroom3 SNPs and illustrates the key cell type involved. In support of this, targeting Shroom3-Rock interaction (between the ASD2 domain of Shroom3 and the Coiled coil domain [CCD] of Rock, which houses the Shroom binding domain) by genetic or pharmacologic means (P2Is) during tubular Shroom3 excess rescues the increased TIF, reflecting the therapeutic potential of this strategy for TIF and CKD progression in at-risk patients. (iPTs -injured proximal tubular cells). Created in BioRender. Caplan, M. (2026) https://BioRender.com/6ykyx16.
