Abstract 110: Reduced Expression, Knockout, and Pharmacological Intervention of Arhgef11 -RhoA Pathway Significantly Attenuates Renal Injury and Blood Pressure

Through genetic analysis of the Dahl salt-sensitive (SS) rat, a model of hypertension and chronic kidney disease (CKD), Arhgef11, a Rho guanine nucleotide exchange factor was implicated in kidney injury. Arhgef11, via exchange of GDP for GTP, plays a role in the activation of RhoA signaling cascades through a number of cell stimuli that impact cytoskeletal structure and influence cell-cell contacts and promotes cell transformation. Previously, we demonstrated that reduced Arhgef11 expression/protein function in an SS- Arhgef11 SHR -minimal congenic strain resulted in significantly decreased proteinuria, fibrosis, and improved renal hemodynamics compared to SS-WT, without impacting BP. More recently, an SS-Arhgef11 -/- knockout rat model was studied. On low-salt (0.3% NaCl), SS-Arhgef11 -/- animals demonstrated reduced proteinuria and renal injury, with no impact on BP versus SS-WT. In contrast, SS-Arhgef11 -/- animals on an elevated-salt diet (2% NaCl) demonstrated a significant (pArhgef11 (on low-salt) similarly leads to renoprotection, whereas the loss of Arhgef11 (vs reduced expression) leads to blunting of salt-induced elevations in BP vs SS-WT. These animal studies, in combination with in vitro work, suggest that inhibition of Arhgef11-RhoA could be an effective therapeutic for CKD. Using an in vitro cell screen, several hundred natural product compounds were tested for ability to inhibit Arhgef11/RhoA activity and identified 3 compounds. A pilot study done using one compound (sufficient for a one-week study) was very encouraging as animals treated with XTL-019-G7 (20mg/kg/day) exhibited an ~25% reduction in proteinuria compared to vehicle (VEH) treated animals (70±8.5 versus 95±9.6 mg/24hours, p=0.07), demonstrating that in vivo testing is feasible and that the compound warrants further testing. In summary, genetic analysis of a model of CKD identified a gene/pathway involved in kidney injury that served as a target to screen natural product derived small molecules, and may ultimately lead to a new treatment for CKD.