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

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.

Pathogenic and protective role of macrophages in kidney disease

“…Other signaling molecules, including suppressor of cytokine signaling 3 (SOCS3) and IKK, have also been reported to be upregulated in kidney M⌽ in nephritis (4,53). Recently, it was reported that kidney M⌽ in UUO highly express mTOR signaling and that rapamycin inhibited inflammatory activity of M⌽ via mTOR signaling (10). However, the signaling pathways involved in M2 M⌽ function in kidney disease remain unclear.…”

Muscle Gene Expression Patterns in Human Rotator Cuff Pathology

“…On the other hand, myostatin (MSTN), which is secreted by muscle, inhibits myogenesis 21 and muscle hypertrophy [22][23][24] (via regulation of mammalian target of rapamycin [MTOR]) but promotes fibrosis 25,26 and adipogenesis 21 . An animal model of rotator cuff injury has also shown that MTOR modulates fatty infiltration 27 , and it regulates fibrosis [28][29][30] . Growth factors such as transforming growth factor b1 (TGFB1) and connective tissue growth factor (CTGF) are considered master regulators of fibrosis, which in simple terms represents an imbalance between the breakdown of extracellular matrix proteins by matrix metalloproteinases (MMPs) and the activity of tissue inhibitors of metalloproteinase (TIMPs), which inhibit MMPs 31 .…”

Shenqi detoxification granule combined with P311 inhibits epithelial-mesenchymal transition in renal fibrosis <i>via</i> TGF-β1-Smad-ILK pathway

“…This finding differs from our data. The relationship between P311 and TGF-β1 might be reasonable to explain this discrepancy, because infiltration of inflammatory cells is an early and characteristic feature of renal fibrosis (37). During renal fibrosis, at early stages of repair with abundant inflammatory cells, the antifibrogenic effect of P311 may be offset by TGF-β1 and exhibit a pro-fibrogenic effect, while at advanced stages of repair while inflammatory cells gradually disappeared, the antifibrogenic effect of P311 may increase over time and become maximal toward the end of the reparative process (18).…”