Cadherin-11 mediates kidney injury through altered renal fibroblast mechanobiology.

Abstract

Cadherin-11 (CDH11) is a mechanosensitive protein capable of creating cell-cell and cell-substrate junctions governing responses to environmental stimuli. It is known to perpetuate fibroblast activation and an inflammatory environment, so we hypothesized that CDH11 is a viable target to suppress kidney injury. Three models were used to test the efficacy of Cdh11 ablation and the CDH11 blocking antibody SYN0012 on kidney injury outcomes in: unilateral ureteral obstruction, aristolochic acid nephropathy, and uninephrectomy with angiotensin II infusion. Kidney fibroblasts were isolated to test CDH11-mediated response to environmental cues. Cytokine arrays were used to quantify secretory changes, and atomic force microscopy was used to measure tissue stiffness. CDH11 increased after injury and was localized to the interstitium. Cdh11-/- mice had reduced fibrosis and decreased circulating levels of inflammatory, fibrotic, and kidney injury markers after unilateral ureteric obstruction. Cdh11-/- mice had improved survival and kidney function (plasma BUN) in the aristolochic acid nephropathy model, while in the uninephrectomy model with angiotensin II infusion, Cdh11-/- mice had improved function and muted cardiorenal injury markers. Contractility and sensitivity to strain in Cdh11-/- kidney fibroblasts were decreased, and these effects are further supported by limited tissue stiffening of the fibrogenic niche after unilateral ureteric obstruction. SYN0012 recapitulated the major findings in all three injury models. Targeting CDH11 attenuates kidney injury in multiple models to improve kidney function, decrease fibrosis and inflammation, and protect from downstream cardiac remodeling. This establishes CDH11 as a major player in renal fibroblast mechanobiology, limiting tissue stiffening and therefore propagation of injury. Hence, CDH11 targeting may be a novel strategy to limit expansion of chronic kidney disease.