Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin-angiotensin system (RAS). We tested the hypothesis that the protection provided by ACE inhibition also decreases capillary rarefaction, lymphangiogenesis and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60mg/kg/day) (ACEi) or vehicle. Proteinuria, blood urea nitrogen and plasma creatinine were regularly assessed and grafts were harvested for morphological and immunohistological analysis at various times up to 32 weeks. In the vehicle group many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 week after transplantation. Lymphangiogenesis increased till week 4 by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction and proteinuria appeared later, at weeks 4-12. The number of lymphatic capillary cross sections strongly correlated with interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis and blood capillary rarefaction at 32 weeks. In conclusion, ACE inhibition considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intra-glomerular pressure lowering effects of ACE inhibition. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACE inhibition.
- blood capillary rarefaction
- renal allograft fibrosis
- ACE inhibition
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology