Thrombospondin-1 short hairpin RNA suppresses tubulointerstitial fibrosis in the kidney of ureteral obstruction by ameliorating peritubular capillary injury.

Background/aims: Thrombospondin-1 (TSP-1), a naturally occurring inhibitor of angiogenesis, is an important mediator of renal fibrosis in clinical and experimental kidney disease. Increasing evidence shows that the microvasculature plays a critical role in progressive renal disease. The present study was undertaken to investigate whether interstitial fibrosis could be prevented by abolishing TSP-1 function in unilateral ureteral obstruction (UUO)-induced renal fibrosis.

Methods And Results: A short hairpin RNA vector, designated Thbs-1, significantly suppressed TSP-1 in both transcriptional and translational levels in in vitro-cultured cells and in vivo fibrosis-induced mouse kidney. Furthermore, TSP-1 RNA interference increased the protein level of vascular endothelial growth factor (VEGF) and the density of peritubular capillaries (PTCs), reduced the expression of hypoxia-inducible factor-1α in tubulointerstitial cells, and collagen III and the connective tissue growth factor expression were markedly reduced from day 7 after UUO-induced fibrosis, but un- or vector-treated mice maintained their expression. TSP-1 shRNA suppressed the protein level of TSP-1, increased VEGF expression and PTC density and alleviated the development of renal interstitial fibrosis in UUO mice.

Conclusion: These data suggest that inhibition of TSP-1 expression prevented tubulointerstitial fibrosis through ameliorating PTC injury.