Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury
- Author(s)
- Susnik, N; Sorensen-Zender, I; Rong, S; von Vietinghoff, S; Lu, X; Rubera, I; Tauc, M; Falk, CS; Alexander, WS; Melk, A; Haller, H; Schmitt, R;
- Details
- Publication Year 2014-01-08,Volume 85,Issue #6,Page 1357-1368
- Journal Title
- Kidney international
- Publication Type
- Journal Article
- Abstract
- Suppressor of cytokine signaling 3 (SOCS-3) is an important intracellular negative regulator of several signaling pathways. We found that SOCS-3 is highly expressed in renal proximal tubules during acute kidney injury. To test the impact of this, conditional proximal tubular knockout mice (SOCS-3sglt2Delta/sglt2Delta) were created. These mice had better kidney function than their wild-type counterparts in aristolochic acid nephropathy and after ischemia/reperfusion injury. Kidneys of these knockout mice showed significantly more proximal tubular cell proliferation during the repair phase. A direct effect of SOCS-3 on tubular cell cycling was demonstrated by in vitro experiments showing a JAK/STAT pathway-dependent antimitotic effect of SOCS-3. Furthermore, acute damaged kidneys of the knockout mice contained increased numbers of F4/80+ cells. Phenotypic analysis of these F4/80+ cells indicated a polarization from classically activated to alternatively activated macrophages. In vitro, SOCS-3-overexpressing renal epithelial cells directly induced classical activation in cocultured macrophages, supporting the observed in vivo phenomenon. Thus, upregulation of SOCS-3 in stressed proximal tubules plays an important role during acute kidney injury by inhibition of reparative proliferation and by modulation of the macrophage phenotype. Antagonizing SOCS-3 could have therapeutic potential for acute kidney injury.Kidney International advance online publication, 8 January 2014; doi:10.1038/ki.2013.525.
- Publisher
- NPG
- Research Division(s)
- Cancer And Haematology
- Publisher's Version
- https://doi.org/10.1038/ki.2013.525
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- © 2014 International Society of Nephrology
Creation Date: 2014-01-24 12:02:23