PP2Ac\u03b1 promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNF\u03b1 production

Yan Liang,Chunsun Dai,Lu Zhou,Mengru Gu,Xian Xue,Qingmiao Lu,Qing Hou,Sudan Wang,Mingjie Wang,Xiaoli Sun,Mengzhu Tan

doi:10.1038/s41418-021-00780-5

Yan Liang, Chunsun Dai + Show 9 more

Open Access

https://doi.org/10.1038/s41418-021-00780-5

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Journal: Cell Death and Differentiation	Publication Date: May 1, 2021
Citations: 13	License type: open-access

Affiliation: Nanjing Medical University

Abstract

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 PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. 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, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα−/− macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.

Highlights

Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, increased urinary albumin excretion, or both, is becoming an increasing public health issue [1]
Western blot analyses revealed that PP2Ac and PP2Acα abundance was markedly increased at day 7 after ureteral occlusion (UUO) and day 14 after ischemia reperfusion injury (IRI), respectively
About 20 and 50% of kidney cells were stained positive for PP2Ac (Fig. 1g), whereas about 6 and 12% of kidney cells were stained positive for F4/80 in UUO and IRI kidneys, respectively (Fig. 1h)

Summary

Introduction

Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, increased urinary albumin excretion, or both, is becoming an increasing public health issue [1]. Regardless of the initial causes of CKD, interstitial fibrosis is the common pathologic characteristic and highly correlated with the long-term prognosis of CKD patients. Fibroblast activation, tubular atrophy, and microvascular rarefaction contribute to renal interstitial fibrosis [2]. Renal fibrosis is always preceded and accompanied by the interstitial

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