Rapamycin Ameliorates Kidney Fibrosis by Inhibiting the Activation of mTOR Signaling in Interstitial Macrophages and Myofibroblasts

Guochun Chen,Fuyou Liu,Hong Liu,Lin Sun,Chang Wang,Youming Peng,Huihui Chen,Bernhard Ryffel

doi:10.1371/journal.pone.0033626

Guochun Chen, Fuyou Liu + Show 6 more

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https://doi.org/10.1371/journal.pone.0033626

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Abstract

Interstitial fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Emerging data indicate that rapamycin can ameliorate kidney fibrosis by reducing the interstitial infiltrates and accumulation of extra cellular matrix (ECM). However, the cellular mechanism that regulates those changes has not been well understood yet. In this study, we revealed the persistent activation of mammalian target of rapamycin (mTOR) signaling in the interstitial macrophages and myofibroblasts, but rarely in injured proximal epithelial cells, CD4+ T cells, neutrophils, or endothelial cells, during the development of kidney fibrosis. Administration of rapamycin to unilateral ureteral obstruction (UUO) mice significantly suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-β1. Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts.

Highlights

Tubulointerstitial fibrosis is the final common pathway of a wide variety of chronic progressive kidney diseases
We characterized the activation pattern of mammalian target of rapamycin (mTOR) signaling in different renal cell types during kidney injury-fibrosis; we evaluated the effect of rapamycin on the fibrogenic activity of cultured fibroblasts, HK2 cells and macrophages isolated from the fibrotic kidneys
Activation of mTOR and significant inflammatory response were induced in infiltrated macrophages post ischemic or obstructed injury, which could be significantly blocked by rapamycin (Figure 6 and Figure 7)

Summary

Introduction

Tubulointerstitial fibrosis is the final common pathway of a wide variety of chronic progressive kidney diseases. Intense studies have focused on the molecular and cellular pathogenesis of interstitial fibrosis due to the strong correlation between the degree of interstitial fibrosis and renal functional loss in CKD. Studies in a wide variety of animal models confirmed that treatment of rapamycin to inhibit mTOR could markedly ameliorate the interstitial inflammation, fibrosis, and loss of renal function associated with CKD [1,2,3,4,5,6,7]. Little has been clarified in these studies upon the cellular targets of rapamycin, regarding its protective role in kidney fibrosis. Progression of renal fibrosis can initially be characterized as induction of inflammatory response and result in widespread fibrotic changes. The regulatory mechanism in these effector cells still remains obscure in kidney fibrosis, which limits the prevention and early interruption in the disease development

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