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Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

¹Division of Nephrology and ⁵Departments of Ophthalmology, Molecular Genetics, and Microbiology, University of Florida, Gainesville, Florida; ²Nephro-Urology Unit, University College London, Institute of Child Health, London, United Kingdom; ³Division of Nephrology, University of Alabama, Birmingham, Alabama; and ⁴Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China

Submitted 22 July 2008 ; accepted in final form 22 October 2008

Angiostatin, a proteolytic fragment of plasminogen, is a potent anti-angiogenic factor recently shown also to have an inhibitory effect on leukocyte recruitment and macrophage migration. Because both angiogenesis and inflammation play key roles in the progression of chronic kidney disease, we evaluated the effect of angiostatin treatment in the rat remnant kidney model. Rats were pretreated for 4 wk with recombinant adeno-associated viruses expressing either angiostatin or green fluorescence protein. Chronic renal disease was then induced by a subtotal nephrectomy, and rats were killed 8 wk later for analysis. Angiostatin treatment was associated with significantly less proteinuria but no alterations in serum creatinine, creatinine clearance, and blood urea nitrogen levels. Treatment with angiostatin reduced renal peritubular capillary number and decreased urinary nitric oxide levels. Despite reducing capillary density, angiostatin diminished interstitial fibrosis in association with reduced macrophage and T-cell infiltration and renal monocyte chemoattractant protein-1 mRNA levels. In conclusion, angiostatin overexpression was associated with attenuated renal disease progression in a model of chronic kidney injury, likely because of its anti-inflammatory actions. However, its anti-angiogenic actions suggest countering effects that could partially offset its benefit in chronic kidney diseases.

angiogenesis; gene therapy; inflammation; macrophage; vascular growth factors

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