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Abstract: SA-PO315

Myeloid PTEN Deficiency Exacerbates Renal Inflammation and Fibrosis in Angiotensin II-Induced Hypertension

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • An, Changlong, University of Connecticut Health Center, Farmington, Connecticut, United States
  • Wen, Jia, University of Connecticut Health Center, Farmington, Connecticut, United States
  • Jiao, Baihai, University of Connecticut Health Center, Farmington, Connecticut, United States
  • Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States
  • Wang, Yanlin, University of Connecticut Health Center, Farmington, Connecticut, United States
Background

Hypertension is a major cause of chronic kidney disease, which is characterized by inflammation, tubular atrophy, and fibrosis. However, the molecular mechanisms that are responsible for the induction of inflammation and fibrosis are not fully understood. In the present study, we examined the role of phosphatase and tensin homolog (PTEN) in the pathogenesis of renal inflammation and fibrosis in an experimental model of hypertension.

Methods

We generated myeloid cell-specific PTEN knockout mice by crossing floxed PTEN mice with LysM-driven Cre mice. Both LysM-Cre-/-PTENf/f mice and LysM-Cre+/+PTENf/f mice were infused with angiotensin II at 1.5ug/kg/min or vehicle for 28 days. To accelerate renal injury, all mice were subjected to unilateral nephrectomy and received 1% sodium chloride in drinking water. Blood pressure was monitored by BP-2000 system. Renal function was evaluated by measuring serum creatinine. Proteinuria was quantified by measuring albumin and creatinine in the urine. Kidney sections were stained for histological and immunological analysis. Western blot analysis and immunostaining were performed to detect the levels of fibronectin, collagen type I, and alpha-SMA in the kidneys. Sirius red staining was performed to examine total collagen deposition in the kidney.

Results

Both LysM-Cre-/-PTENf/f mice and LysM-Cre+/+PTENf/f mice had comparable blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that is similar between LysM-Cre-/-PTENf/f mice and LysM-Cre+/+PTENf/f mice. Compared with LysM-Cre-/-PTENf/f mice, LysM-Cre+/+PTENf/f mice developed significantly worse renal dysfunction, proteinuria, and fibrosis following angiotensin II treatment. PTEN deficiency in myeloid cells enhanced myeloid fibroblast accumulation and myofibroblast formation associated with a significant increase in total collagen deposition and extracellular matrix protein production in the kidneys in response to angiotensin II. Immunohistochemical analysis revealed that PTEN deficiency in myeloid cells augmented infiltration of F4/80+ macrophages and CD3+ T cells into the kidneys of angiotensin II-treated mice.

Conclusion

PTEN plays a crucial role in the development of hypertensive kidney inflammation and fibrosis trough regulation of macrophage and T cell infiltration and myeloid fibroblast accumulation.

Funding

  • NIDDK Support