Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism.
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.
Mu
Wei
W
Division of Nephrology, University of Florida, Gainesville, FL, USA.
Long
David A
DA
Ouyang
Xiaosen
X
Agarwal
Anupam
A
Cruz
Pedro E
PE
Roncal
Carlos A
CA
Nakagawa
Takahiko
T
Yu
Xueqing
X
Hauswirth
William W
WW
Johnson
Richard J
RJ
D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000652:urine; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D043168:Angiostatins; D003404:Creatinine