Shroom3-Rock interaction and profibrotic function: mechanism and precision therapeutics for an intronic CKD risk allele.

Enhancer SNPs in Shroom3 associate with renal fibrosis (TIF), and with reduced albuminuria. Detailed mechanisms for these pleiotropic effects are unclear. Here, we focused on identifying the specific profibrotic Shroom3 motif and separating this from its anti-proteinuric function. Given the role for Rho-kinases (Rock) in TIF, and the interaction of Rock with Shroom3 ASD2-domain, we hypothesized that Shroom3-mediated Rock-activation is crucial for profibrotic function. To test this, we developed transgenic tools that overexpress wild-type-(WT-Sh3) or ASD2-domain deletion-Shroom3 (ASD2D-Sh3). In vivo, inducible global-, or tubular-specific-, but not fibroblast-specific-, ASD2D-Sh3 overexpression mitigated TIF, vs WT-Sh3 overexpression. Aristolochic acid nephropathy (AAN) was the model used for simulating injury followed by tissue remodeling and ultimately fibrosis.