PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production

Macrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Ac alpha in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Ac alpha. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Ac alpha deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Ac alpha(-/-) macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor alpha (TNF alpha) production in macrophages. Together, this study demonstrates that PP2Ac alpha promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNF alpha production.

Automated summary

The study found that PP2Ac alpha promotes macrophage accumulation and activation, accelerating kidney fibrosis. Deleting PP2Ac alpha can reduce kidney fibrosis and related damage. In vitro experiments also showed that PP2Ac alpha deficiency decreases cell motility.