Abstract: SA-PO1095

Phosphoinositide-3 Kinase γ Regulates Inflammation and Renal Fibrosis in Angiotensin II-Induced Hypertension

Session Information

Category: Hypertension

  • 1101 Hypertension: Basic and Experimental - Neural and Inflammatory Mechanisms

Authors

  • An, Changlong, Baylor College of Medicine, Houston, Texas, United States
  • Thomas, Sandhya S., Baylor College of Medicine, Houston, Texas, United States
  • Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
  • Wang, Yanlin, Baylor College of Medicine, Houston, Texas, United States
Background

We have recently shown that CXCL16/CXCR6 axis plays a critical role in recruiting inflammatory cells and bone marrow-derived fibroblasts into the kidney resulting in renal injury and fibrosis. However, the underlying signaling mechanisms are not known. In the present study, we examined the role of phosphoinositide-3 kinase γ (PI3Kγ) in 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.

Methods

Wild-type (WT) and PI3Kγ knockout (KO) mice were treated with angiotensin II via subcutaneous osmotic minipumps at 1500 ng/kg/min for 4 weeks following uninephrectomy. All the mice were given 1% NaCl in drinking water ad lib. Blood pressure, kidney function, proteinuria, and renal histology were evaluated. Immunostaining was performed to examine the number of inflammation cells and myeloid fibroblasts in the kidney. Proinflammatroy molecule expression was assessed by rela-time RT-PCR. Renal fibrosis and extracellular matrix protein production were determined by sirius red staining, immunostaining and Western blot. Transwell migration assay was performed to determine the role of PI3Kγ in the regulation of cell migration in vitro.

Results

WT and PI3Kγ KO mice had virtually identical blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that is 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 ECM protein production in the kidney in response to angiotensin II. PI3Kγ deficiency inhibited infiltration of F4/80+ macrophages and CD3+ T cells into the kidney and reduced gene expression levels of proinflammatory cytokines in the kidney following angiotensin II treatment. Inhibition of PI3Kγ with AS605240 suppressed CXCL16-induced Akt activation and monocyte migration in vitro.

Conclusion

Our results indicate that PI3Kγ plays a pivotal role in the development of hypertensive kidney injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation.

Funding

  • NIDDK Support