Changlong An1, Jia Wen1, Zhaoyong Hu2, William E Mitch2, Yanlin Wang1,3,4,5. 1. Division of Nephrology, Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA. 2. Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 3. Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA. 4. Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT, USA. 5. Renal Section, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
Abstract
BACKGROUND: We have shown that the CXCL16/CXCR6 axis plays a critical role in recruiting inflammatory cells and bone marrow-derived fibroblasts into the kidney leading to renal injury and fibrosis. However, the underlying signaling mechanisms are not known. METHODS: In the present study, we examined the role of phosphoinositide-3 kinase γ (PI3Kγ) signaling in the recruitment of inflammatory cells and bone marrow-derived fibroblasts into the kidney and development of renal injury and fibrosis in an experimental model of hypertension induced by angiotensin II. RESULTS: Blood pressure was comparable between wild-type (WT) and PI3Kγ knockout (KO) mice at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between WT and PI3Kγ KO mice. Compared with WT mice, PI3Kγ KO mice were protected from angiotensin II-induced renal dysfunction and injury and developed less proteinuria. PI3Kγ deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidney and inhibited total collagen deposition and extracellular matrix protein production in the kidney in response to angiotensin II. PI3Kγ deficiency inhibited the infiltration of F4/80+ macrophages and CD3+ T cells into the kidney and reduced gene expression levels of pro-inflammatory cytokines in the kidney following angiotensin II treatment. Finally, inhibition of PI3Kγ suppressed CXCL16-induced monocyte migration in vitro. CONCLUSION: These results indicate that PI3Kγ mediates the influx of macrophages, T cells and bone marrow-derived fibroblasts into the kidney resulting in kidney injury and fibrosis. Published by Oxford University Press on behalf of ERA-EDTA 2020. This work is written by US Government employees and is in the public domain in the US.
BACKGROUND: We have shown that the CXCL16/CXCR6 axis plays a critical role in recruiting inflammatory cells and bone marrow-derived fibroblasts into the kidney leading to renal injury and fibrosis. However, the underlying signaling mechanisms are not known. METHODS: In the present study, we examined the role of phosphoinositide-3 kinase γ (PI3Kγ) signaling in the recruitment of inflammatory cells and bone marrow-derived fibroblasts into the kidney and development of renal injury and fibrosis in an experimental model of hypertension induced by angiotensin II. RESULTS: Blood pressure was comparable between wild-type (WT) and PI3Kγ knockout (KO) mice at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between WT and PI3Kγ KO mice. Compared with WT mice, PI3Kγ KO mice were protected from angiotensin II-induced renal dysfunction and injury and developed less proteinuria. PI3Kγ deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidney and inhibited total collagen deposition and extracellular matrix protein production in the kidney in response to angiotensin II. PI3Kγ deficiency inhibited the infiltration of F4/80+ macrophages and CD3+ T cells into the kidney and reduced gene expression levels of pro-inflammatory cytokines in the kidney following angiotensin II treatment. Finally, inhibition of PI3Kγ suppressed CXCL16-induced monocyte migration in vitro. CONCLUSION: These results indicate that PI3Kγ mediates the influx of macrophages, T cells and bone marrow-derived fibroblasts into the kidney resulting in kidney injury and fibrosis. Published by Oxford University Press on behalf of ERA-EDTA 2020. This work is written by US Government employees and is in the public domain in the US.
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